Biologically active acylated amino acid derivatives

ABSTRACT

The present invention relates to novel compounds which possess a broad range of useful biological activities. These compounds can maintain, increase, or restore sensitivity of cells to therapeutic or prophylactic agents. They can also suppress, modify, or significantly reduce an immune response, including an autoimmune response in a mammal. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well-suited for treatment of multi-drug resistant cells, for prevention of the development of multi-drug resistance, for use in multi-drug resistant cancer therapy, and for prevention or treatment of graft rejection and various autoimmune diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation-in-part of U.S. application Ser. No. 08/127,814,filed Sep. 28, 1993 and now abandoned, which is a continuation-in-partof U.S. application Ser. No. 07/952,299, filed Sep. 28, 1992, nowabandoned. This is also a continuation-in-part of U.S. application Ser.No. 07/881,152, filed May 11, 1992 and now abandoned, which is acontinuation-in-part of U.S. application Ser. No. 07/697,785, filed May9, 1991, now abandoned.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to novel compounds which possess a broadrange of useful biological activities. These compounds can maintain,increase, or restore sensitivity of cells to therapeutic or prophylacticagents. They can also suppress or modify the immune response in humansand other mammals. This invention also relates to pharmaceuticalcompositions comprising these compounds. The compounds andpharmaceutical compositions of this invention are particularlywell-suited for treatment of multi-drug resistant cells, for preventionof the development of multi-drug resistance and for use in multi-drugresistant cancer therapy. In addition, the compounds and pharmaceuticalcompositions of this invention are useful for prevention, suppression orreduction of graft rejection, as well as the treatment or prevention ofautoimmune diseases.

BACKGROUND OF THE INVENTION

Two important areas of medicine are cancer chemotherapy and chemicalmodifications of the immune system. These have been the focus of muchrecent medical research.

A major problem affecting the efficacy of chemotherapy regimens is theevolution of cells which, upon exposure to a chemotherapeutic drug,become resistant to a multitude of structurally unrelated drugs andtherapeutic agents. The appearance of such multi-drug resistance oftenoccurs in the presence of overexpression of the 170-kDA membraneP-glycoprotein (gp-170). The gp-170 protein is present in the plasmamembranes of some healthy tissues, in addition to cancer cell lines, andis homologous to bacterial transport proteins (Hait et al., CancerCommunications, Vol. 1(1), 35 (1989); West, TIBS, Vol. 15, 42 (1990)).The protein acts as an export pump, conferring drug resistance throughactive extrusion of toxic chemicals. Although the mechanism for the pumpis unknown, it is speculated that the gp-170 protein functions byexpelling substances that share certain chemical or physicalcharacteristics, such as hydrophobicity, the presence of carbonylgroups, or the existence of a glutathione conjugate (see West).

Various chemical agents have been administered to repress multi-drugresistance and restore drug sensitivity. While some drugs have improvedthe responsiveness of multi-drug resistant ("MDR") cells tochemotherapeutic agents, they have often been accompanied by undesirableclinical side effects (see Hait et al.). For example, althoughcyclosporin A ("CsA"), a widely accepted immunosuppressant, cansensitize certain carcinoma cells to chemotherapeutic agents (Slater etal., Br. J. Cancer, Vol. 54, 235 (1986)), the concentrations needed toachieve that effect produce significant immunosuppression in patientswhose immune systems are already compromised by chemotherapy (see Haitet al.). In addition, CsA usage is often accompanied by adverse sideeffects including nephrotoxicity, hepatotoxicity and central nervoussystem disorders. Similarly, calcium transport blockers and calmodulininhibitors both sensitize MDR cells, but each produces undesirablephysiological effects (see Hait et al.; Twentyman et al., Br. J. Cancer,Vol. 56, 55 (1987)).

Recent developments have led to agents said to be of potentially greaterclinical value in the sensitization of MDR cells. These agents includeanalogs of CsA which do not exert an immunosuppressive effect, such as11-methyl-leucine cyclosporin (11-met-leu CsA) (see Hait et al.;Twentyman et al.), or agents that may be effective at low doses, such asthe immunosuppressant FK-506 (Epand and Epand, Anti-Cancer Drug Design6, 189 (1991)). Despite these developments, the need remains foreffective agents which may be used to resensitize MDR cells totherapeutic or prophylactic agents or to prevent the development ofmulti-drug resistance.

A second significant medical objective constitutes the ability tomodulate the immune system. For example, post operative graft rejectionsare a major complication affecting the success of bone marrow and organtransplantations. However, through the use of immunosuppressive drugtherapy, graft rejection in organ transplantation can be significantlyreduced. Immunosuppressive therapy may also be used in preventing ortreating autoimmune diseases, which are similar to graft rejection,except that the rejection is of self tissue.

One widely accepted immunosuppressant for the prevention of graftrejection is CsA. A natural product of fungal metabolism, CsA has beendemonstrated to have potent immunosuppressive activity in clinical organtransplantations. Calne, R. Y. et al., Br. Med. J., Vol. 282, pp.934-936 (1981); White, D. J. C., Drugs, Vol. 24, pp. 322-334 (1982).

Many disorders have been treated with cyclosporin A with positiveresults, confirming the importance of the autoimmune component in thesediseases and their effective treatment with compounds working byselective T-cell immune suppression similar to cyclosporin A. Thesedisorders include ophthalmological diseases, such as uveitis,Nussenblatt, R. B. et al., Lancet, pp. 235-238 (1983); Behcet'sdisease,* French-Constant, C. et al., Lancet, p. 454 (1983); Sanders, M.et al., Lancet, pp. 454-455 (1983); and Grave's ophthalmopathy, Weetman,A. P. et al., Lancet, pp. 486-489 (1982).

CsA has also been used in dermatological applications, including variousautoimmune skin diseases, such as psoriasis, Ellis, C. N. et al., J.Amer. Med. Assoc., Vol. 256, pp. 3110-3116 (1986); Griffiths, C. E. M.et al., Brit. Med. J., Vol. 293, pp. 731-732 (1986); acutedermatomyositis, Zabel, P. et al., Lancet, p. 343 (1984); atopic skindisease, van Joost, T. et al., Arch. Dermatol., Vol. 123, pp. 166-167(1987); scleroderma, Appleboom, T. et al., Amer. J. Med, Vol. 82, pp.866-867 (1987); and eczema, Logan, R. A. and Camo R. D. R., J. Roy. Soc.Med., Vol. 81, pp. 417-418 (1988).

Various hematological diseases treated with CsA include anemia, such asaplastic anemia, Stryckmans, P. A. et al., New Engl. J. Med., Vol. 310,pp. 655-656 (1984); and Gluckman, E. et al., Bone Marrow Transplant,Vol. 3 Suppl. 1, 241 (1988); and pure red cell aplasia (PRCA),Toetterman, T. H. et al., Lancet, p. 693 (1984).

CsA has also been used in the fields of gastroenterology and hepatologyto treat primary cirrhosis, Wiesner, R. H. et al., Hepatology, Vol. 7,p. 1025, Abst. #9 (1987); autoimmune hepatitis, Hyams, J. S. et al.,Gastroenterology, Vol. 93, pp. 890-893 (1987); ulcerative colitis,Porro, G. B. et al., Ital. J. Gastroenterol., Vol. 19, pp. 40-41 (1987);Crohn's disease, Allison, M. C. et al., Lancet, pp. 902-903 (1984), andBrynskov, J. et al., Gastroenterology, Vol. 92, p. 1330 (1987); andother gastrointestinal autoimmune diseases.

Neurological applications of CsA include amyotrophic lateral sclerosis(ALS, "Lou Gehrig's disease"), Appel, S. H. et al., Arch. Neurol., Vol.45, pp. 381-386 (1988); myasthenia gravis, Tindall, R. S. A. et al., NewEngl. J. Med., Vol. 316, pp. 719-724 (1987); and multiple sclerosis,Ann. Neurol., Vol. 24, No. 1, p. 169,m Abstract P174 (1988), andDommasch, D. et al., Neurology, Vol. 38 Suppl. 2, pp. 28-29 (1988).

CsA has been used to treat nephrotic syndromes, membrano-proliferativeglomerulonephritis (MPGN) and related diseases, Watzon, A. R. et al.,Clin. Nephrol., Vol. 25, pp. 273-274 (1986); Tejani, A. et al., KidneyInt., Vol. 33, pp. 729-734 (1988); Meyrier, A. et al., Transplat Proc.,Vol. 20, Suppl. 4 (Book III), pp. 259-261 (1988); LaGrue, G. et al.,Nephron., Vol. 44, pp. 382-382 (1986).

In addition, CsA has been used to treat rheumatoid arthritis, Harper, J.I. et al., Lancet, pp. 981-982 (1984); Van Rijthoven, A. W. et al., Ann.Rheum. Dis., Vol. 45, pp. 726-731 (1986), and Dougados, M. et al., AnnRheum. Dis., Vol. 47, pp. 127-133 (1988); and insulin-dependent diabetesmellitus (IDDM), Stiller, C. R. et al., Science, Vol. 233, pp. 1362-1367(1984), Assan, R. et al., Lancet, pp. 67-71 (1985); Bougneres, P. F. etal., New Engl. J. Med., Vol. 318, pp. 663-670 (1988), and Diabetes, Vol.37, pp. 1574-1582 (1988).

Many veterinary diseases are also characterized as autoimmune diseases.Autoimmune diseases such as those discussed above have been observed inmammals. Papa, F. O. et al., Equine Vet. J., Vol. 22, pp. 145-146(1990)--infertility of autoimmune origin in the stallion; Gorman, N. T.and L. L. Werner, Brit. Vet. J., Vol. 142, pp. 403-410, 491-497 and498-505 (1986)--immune mediated diseases of cats and dogs; George, L. W.and S. L White, Vet. Clin. North Amer., Vol. 6, pp. 209-213(1984)--autoimmune skin diseases in large mammals; Bennett, D., In.Pract., Vol. 6, pp. 74-86 (1984)--autoimmune diseases in dogs;Halliwell, R. E., J. Amer. Vet. Assoc., Vol. 181, pp. 1088-1096(1982)--autoimmune diseases in domesticated animals.

The mechanism by which CsA causes immunosuppression has beenestablished. In vitro, CsA inhibits the release of lymphokines, such asinterleukin 2 (IL-2) [Bunjes, D. et al., Eur. J. Immunol., Vol. 11, pp.657-661 (1981)] and prevents clonal expansion of helper and cytotoxic Tcells [Larsson, E., J. Immunol., Vol. 124, pp. 2828-2833 (1980)]. CsAhas been shown to bind the cytosolic protein, cyclophilin, and inhibitthe prolyl-peptidyl cis-trans isomerase (PPIase) activity of thatprotein. Fischer, G. et al., Nature, Vol. 337, pp. 476-478 (1989);Takashaski, N. et al., Nature, Vol. 337, pp. 473-475 (1989).

Recently, a second natural product isolated from Streptomyces, referredto as FK-506, has been demonstrated to be a potent immunosuppressiveagent. Tanaka, H. et al., J. Am. Chem. Soc., Vol. 109, pp. 5031-5033(1987). FK-506 inhibits IL-2 production, inhibits mixed lymphocyteculture response and inhibits cytotoxic T-cell generation in vitro at100 times lower concentration than cyclosporin A. Kino, T. et al., J.Antibiot., Vol. 15, pp. 1256-1265 (1987). FK-506 also inhibits PPIaseactivity, but is structurally different from CsA and binds to a bindingprotein (FKBP) distinct from cyclophilin. Harding, M. W. et al., Nature,Vol. 341, pp. 758-760 (1989); Siekierka, J. J., Nature, Vol. 341, pp.755-757 (1989).

In view of the wide variety of disorders that may be alleviated byimmunosuppression, and the scant number of available immunosuppressants,there remains a great need for novel immunosuppressive agents. Suchagents may be used alone or serve as supplemental therapeutics to CsAand FK-506.

SUMMARY OF THE INVENTION

The present invention provides novel compounds that are useful tomaintain, increase or restore drug sensitivity in multi-drug resistant("MDR") cells, compositions containing those compounds and methods forusing them. The compounds of this invention may be used alone or incombination with other therapeutic or prophylactic agents to maintain,increase or restore the therapeutic or prophylactic effects of drugs incells, especially MDR cells, or to prevent the development of MDR cells.According to one embodiment of this invention, these novel compounds,compositions and methods are advantageously used to aid or enhancechemotherapy regimens for the treatment or prophylaxis of cancer andother diseases.

The novel compounds of this invention are also useful to prevent,suppress or significantly reduce an immune response in a mammal. Theirability to bind to the FK-506 binding protein (FKBP) allowsimmunosuppressive compounds of this invention, once bound to FKBP, toinhibit T-cell activation. Thus, the compounds of this invention canalso be used as immunosuppressive drugs to prevent or significantlyreduce graft rejection in bone marrow and organ transplantations and inthe treatment or prevention of autoimmune diseases in humans and othermammals.

The present invention also provides methods for preparing the compoundsof this invention and intermediates useful in those methods.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to a novel class of compounds represented by theformula (I): ##STR1## wherein A is CH₂, oxygen, NH or N--(C1-C4 alkyl);wherein B and D are independently:

(i) hydrogen, Ar₁, (C1-C10)-straight or branched alkyl,(C2-C10)-straight or branched alkenyl or alkynyl, (C5-C7)-cycloalkylsubstituted (C1-C6)-straight or branched alkyl, (C2-C6)-straight orbranched alkenyl or alkynyl, (C5-C7)-cycloalkenyl substituted(C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenylor alkynyl, or Ar₁ substituted (C1-C6)-straight or branched alkyl,(C2-C6)-straight or branched alkenyl or alkynyl wherein, in each case,any one of the CH₂ groups of said alkyl, alkenyl or alkynyl chains maybe optionally replaced by a heteroatom selected from the groupconsisting of O, S, SO, SO₂, N, and NR, wherein R is selected from thegroup consisting of hydrogen, (C1-C4)-straight or branched alkyl,(C2-C4)-straight or branched alkenyl or alkynyl, and (C1-C4) bridgingalkyl wherein a bridge is formed between the nitrogen and a carbon atomof said heteroatom-containing chain to form a ring, and wherein saidring is optionally fused to an Ar₁ group; or ##STR2## wherein Q ishydrogen, (C1-C6)-straight or branched alkyl or (C2-C6)-straight orbranched alkenyl or alkynyl;

wherein T is Ar₁ or substituted 5-7 membered cycloalkyl withsubstituents at positions 3 and 4 which are independently selected fromthe group consisting of oxo, hydrogen, hydroxyl, O--(C1-C4)-alkyl, andO--(C2-C4)-alkenyl;

wherein Ar₁ is a carbocyclic aromatic group selected from the groupconsisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl,fluorenyl, anthracenyl, and mono and bicyclic heterocyclic ring systemswith individual ring sizes being 5 or 6 which may contain in either orboth rings a total of 1-4 heteroatoms independently selected fromoxygen, nitrogen, and sulfur - such ring systems include heterocyclicaromatic groups selected from the group consisting of 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyraxolyl, 2-pyrazolinyl,pyrazolidinyl, isoxazolyl, isotiazolyl, 1,2,3-oxadiazolyl,1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl,pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolylo,isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, benzo[b]thiophenyl,1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl,quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, and phenoxazinyl;

wherein any occurrence of Ar₁ may contain one to three substituentswhich are independently selected from the group consisting of hydrogen,halogen, hydroxyl, nitro, trifluoromethyl, trifluoromethoxy,(C1-C6)-straight or branched alkyl, (C2-C6)-straight or branchedalkenyl, O--(C1-C4)-straight or branched alkyl, O--(C2-C4)-straight orbranched alkenyl, O-benzyl, O-phenyl, 1,2-methylenedioxy, amino,carboxyl, N-(C1-C5-straight or branched alkyl or alkenyl) carboxamides,N,N-di-(C1-C5-straight or branched alkyl or C2-C5-straight or branchedalkenyl)carboxamides, N-morpholinocarboxamide, N-benzylcarboxamide,N-thiomorpholinocarboxamide, N-picolinoylcarboxamide, O--X, CH₂--(CH₂)_(q) --X, O--(CH₂)_(q) --X, (CH₂)_(q) --O--X, and CH═CH--X;wherein X is 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl,quinolyl, 3,5-dimethylisoxazoyl, isoxazoyl, 2-methylthiazoyl, thiazoyl,2-thienyl, 3-thienyl, or pyrimidyl, and q is 0-2;

wherein L is U; M is either oxygen or CH--U, provided that if L ishydrogen, then M is CH--U or if M is oxygen then L is not hydrogen;

wherein U is hydrogen, O--(C1-C4)-straight or branched alkyl orO--(C2-C4)straight or branched alkenyl, (C1-C6)-straight or branchedalkyl or (C2-C6)-straight or branched alkenyl, (C5-C7)-cycloalkyl or(C5-C7)-cycloalkenyl substituted with (C1-C4)-straight or branched alkylor (C2-C4)-straight or branched alkenyl, [(C1-C4)-alkyl or(C2-C4)-alkenyl]--Y or Y;

wherein Y is selected from the group consisting of phenyl, 1-naphthyl,2-naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, 2-pyrrolinyl,3-pyrrolinyl, pyrolidinyl, 1,3-dioxolyl, 2-imidazolinyl, imidazolidinyl,2H-pyranyl, 4H-pyranyl, piperidyl, 1,4-dioxanyl, morpholinyl,1,4-dithianyl, thiomorpholinyl, piperazinyl, quinuclidinyl, andheterocyclic aromatic groups as defined above;

where Y may contain one to three substituents which are independentlyselected from the group consisting of hydrogen, halogen, hydroxyl,hydroxymethyl, nitro, trifluoromethyl, trifluoromethoxy,(C1-C6)-straight or branched alkyl, (C1-C6)-straight or branchedalkenyl, O--(C1-C4)-straight or branched alkyl, O--(C2-C4)-straight orbranched alkenyl, O-benzyl, O-phenyl, 1,2-methylenedioxy, amino, andcarboxyl;

wherein J is hydrogen, (C1-C2) alkyl or benzyl; K is (C1-C4)-straight orbranched alkyl, benzyl or cyclohexylmethyl, or wherein J and K may betaken together to form a 5-7 membered heterocyclic ring which maycontain a heteroatom selected from the group consisting of O, S, SO andSO₂ ; and

wherein m is 0-3.

The stereochemistry at positions 1 and 2 (formula I) may beindependently R or S.

In one embodiment of this invention, B and D are independently Ar₂,(C5-C7)-cycloalkyl substituted (C1-C6)-straight or branched alkyl or(C2-C6)-straight or branched alkenyl, (C5-C7)-cycloalkenyl substituted(C1-C6)-straight or branched alkyl or (C2-C6)-straight or branchedalkenyl, or Ar₂ substituted (C1-C6)-straight or branched alkyl or(C2-C6)-straight of branched alkenyl, wherein in each case, any one ofthe CH₂ groups of said alkyl or alkenyl chains is optionally replaced bya heteroatom selected from the group consisting of oxygen, sulfur, SOand SO₂ ; or ##STR3## and Ar₂ is selected from the group consisting ofphenyl, 1-naphthyl, 2-naphtyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, monocyclic and bicyclic heterocyclicring systems with individual ring sizes being 5 or 6 which may containin either or both rings a total of 1-4 heteroatoms independentlyselected from oxygen, nitrogen and sulfur; wherein Ar₂ may contain oneto three substituents which are independently selected from the groupconsisting of hydrogen, halogen, hydroxyl, nitro, trifluoromethyl,trifluoromethoxy, (C1-C6)-straight or branched alkyl, (C1-C6)-straightor branched alkenyl, O--(C2-C4)-straight or branched alkyl,O-(C2-C4)-straight or branched alkenyl, O-benzyl, O-phenyl,1,2-methylenedioxy, amino, carboxyl and phenyl;

and U is hydrogen, O--(C1-C4)-straight or branched alkyl,O--(C1-C4)-straight or branched alkenyl, (C1-C6)-straight or branchedalkyl, (C1-C6)-straight or branched alkenyl, (C5-C7)-cycloalkyl,(C5-C7)cycloalkenyl substituted with (C1-C4)-straight or branched alkylor (C2-C4)-straight or branched alkenyl, [(C1-C4)-alkyl or(C2-C4)-alkenyl]-Ar₂ or Ar₂ (Ar₂ as defined above). In anotherembodiment of this invention, the Ar group in the previous paragraph mayalso contain a hydroxymethyl substituent.

Preferably, at least one of B or D is independently a straight chainterminated by an aryl group, i.e., a group represented by theformula--(CH₂)_(r) --(X)--(CH₂)_(s) --Ar, wherein

r is 0-4;

s is 0-1;

Ar is Ar₁ or Ar₂ ; and

each X is independently selected from the group consisting of CH₂, O, S,SO, SO₂, N, and NR, wherein R is selected from the group consisting ofhydrogen, (C1-C4)-straight or branched alkyl, (C2-C4)-straight orbranched alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein a bridgeis formed between the nitrogen atom and the Ar group.

According to one embodiment of this invention, the heterocyclic aromaticgroups are selected from the group consisting of furan, thiophene,pyrrole, pyridine, indolizine, indole, isoindole, benzo[b]furan,benzo[b]thiophene, 4H-quinolizine, quinoline, isoquinoline,1,2,3,4-tetrahydroquinoline, isoxazole, and1,2,3,4-tetrahydroisoquinoline.

According to another embodiment of this invention, at least one of B orD is selected from the group consisting of (C2-C10)-straight or branchedalkynyl, (C5-C7)-cycloalkyl substituted (C2-C6)-straight or branchedalkynyl, (C5-C7)-cycloalkenyl substituted (C2-C6)-straight or branchedalkynyl, and Ar₁ substituted (C2-C6)-straight or branched alkynyl.

Also within the scope of this invention are compounds of formula (I),wherein at least one of B or D is selected from the group consisting ofAr', Ar'-substituted (C1-C6)-straight or branched alkyl, andAr'-substituted (C2-C6)-straight or branched alkenyl or alkynyl; whereinAr' is an Ar₁ group substituted with one to three substituents which areindependently selected from the group consisting of N-(straight orbranched C1-C5 alkyl or C2-C5 alkenyl) carboxamides, N,N-di-(straight orbranched C1-C5 alkyl or C2-C5 alkenyl)carboxamides,N-morpholinocarboxamide, N-benzylcarboxamide,N-thiomorpholinocarboxamide, N-picolinoylcarboxamide, O--X, CH₂--(CH₂)_(q) --X, O--(CH₂)_(q) --X, (CH₂)_(q) --O--X, and CH═CH--X;wherein X is 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl,quinolyl, 3,5-di-methylisoxazoyl, isoxazoyl, 2-methylthiazoyl, thiazoyl,2-thienyl, 3-thienyl, and pyrimidyl, and wherein q is 0-2.

Examples of some preferred compounds of formula (I), wherein J and K aretaken together to form a 5-7 membered heterocyclic ring, are shown inTable 1 and are further illustrated in the examples herein.

                                      TABLE 1                                     __________________________________________________________________________     ##STR4##                          (II)                                       Cpd.                                                                              n m B         D          U                                                __________________________________________________________________________    2   1 0 3-(Pyridin-2-                                                                           3-Phenylpropyl                                                                           3,4,5-                                                   yl)propyl            Trimethoxyphenyl                                 3   2 0 3-Phenylpropyl                                                                          3-Phenylpropyl                                                                           3,4,5-                                                                        Trimethoxyphenyl                                 4   2 0 3-Phenoxyphenyl                                                                         3-Phenylpropyl                                                                           3,4,5-                                                                        Trimethoxyphenyl                                 5   2 0 Phenyl    2-Phenoxyphenyl                                                                          3,4,5-                                                                        Trimethoxyphenyl                                 6   2 0 Phenyl    3-Phenylpropyl                                                                           3,4,5-                                                                        Trimethoxyphenyl                                 7   2 0 2-(Pyridin-3-                                                                           3-Phenylpropyl                                                                           3,4,5-                                                   yl)ethyl             Trimethoxyphenyl                                 8   2 0 E-3-[trans-(4-                                                                          3-Phenylpropyl                                                                           3,4,5-                                                   Hydroxycyclo-        Trimethoxyphenyl                                         hexyl)]-2-methyl-                                                             eth-2-enyl                                                            9   2 0 3-(Pyridin-3-                                                                           3-Phenylpropyl                                                                           3,4,5-                                                   yl)propyl            Trimethoxyphenyl                                 10  2 0 Benzyl    3-Phenylpropyl                                                                           3,4,5-                                                                        Trimethoxyphenyl                                 11  2 0 Benzyl    3-(3-      3,4,5-                                                             indolyl)propyl                                                                           Trimethoxyphenyl                                 12  2 0 2-Phenylethyl                                                                           3-Phenylpropyl                                                                           3,4,5-                                                                        Trimethoxyphenyl                                 13  2 0 2-(4-Methoxy-                                                                           3-Phenylpropyl                                                                           3,4,5-                                                   phenyl)ethyl         Trimethoxyphenyl                                 14  2 0 2-(4-Methoxy-                                                                           3-Phenylpropyl                                                                           Phenyl                                                   phenyl)ethyl                                                          15  2 0 3-(N-benzimida-                                                                         3-Phenylpropyl                                                                           3,4,5-                                                   zolyl)propyl         Trimethoxyphenyl                                 16  2 1 Benzyl    2-Phenylethyl                                                                            3,4,5-                                                                        Trimethoxyphenyl                                 17  2 0 3-(4-Methoxy-                                                                           3-Phenylpropyl                                                                           3,4,5-                                                   phenyl)propyl        Trimethoxyphenyl                                 18  2 0 3-(Pyridin-3-yl)-                                                                       3-Phenylpropyl                                                                           Phenyl                                                   propyl                                                                19  2 0 3-(Pyridin-2-yl)-                                                                       3-Phenylpropyl                                                                           Phenyl                                                   propyl                                                                20  2 0 3-(Pyridin-2-yl)-                                                                       3-Phenylpropyl                                                                           3,4,5-                                                   propyl               Trimethoxyphenyl                                 21  2 0 3-(Pyridin-2-yl)-                                                                       3-Phenylpropyl                                                                           tert-Butyl                                               propyl                                                                22  2 0 3-(Pyridin-2-yl)                                                                        3-Phenylpropyl                                                                           3,4,5-                                                   propyl N-oxide       Trimethoxyphenyl                                 23  2 0 3-[N-(7-  3-Phenylpropyl                                                                           3,4,5-                                                   azaindolyl)-propyl   Trimethoxyphenyl                                 24  2 0 3-(Pyridin-3-yl)-                                                                       3-(4-      3,4,5-                                                   propyl    Methoxyphenyl)prop                                                                       Trimethoxyphenyl                                                   yl                                                          25  2 0 3-(N-     3-Phenylpropyl                                                                           3,4,5-                                                   Purinyl)propyl       Trimethoxyphenyl                                 26  2 0 3-(4-     3-Phenylpropyl                                                                           3,4,5-                                                   Hydroxymethyl-       Trimethoxyphenyl                                         phenyl)propyl                                                         27  2 0 3-(Pyridin-3-yl)-                                                                       3-Phenylpropyl                                                                           3-Benzyloxyphenyl                                        propyl                                                                28  2 0 3-(Pyridin-3-yl)-                                                                       3-Phenylpropyl                                                                           3-Allyloxyphenyl                                         propyl                                                                29  2 0 3-(Pyridin-3-yl)-                                                                       3-Phenylpropyl                                                                           3-Isopropoxyphenyl                                       Propyl                                                                30  2 0 3-(Thiophen-2-yl)-                                                                      3-Phenylpropyl                                                                           3,4,5-                                                   propyl               Trimethoxyphenyl                                 31  2 0 3-(4-Carboxyphen-                                                                       3-Phenylpropyl                                                                           3,4,5-                                                   yl)propyl            Trimethoxyphenyl                                 32  2 0 3-Phenylbutyl                                                                           3-Phenylpropyl                                                                           3,4,5-                                                                        Trimethoxyphenyl                                 33  2 0 2-Hydroxymethyl-                                                                        3-Phenylpropyl                                                                           3,4,5-                                                   phenyl               Trimethoxyphenyl                                 34  2 0 3-Allyloxyphenyl                                                                        3-Phenylpropyl                                                                           3,4,5-                                                                        Trimethoxyphenyl                                 35  2 0 3-(3-Hydroxymeth-                                                                       3-Phenylpropyl                                                                           3,4,5-                                                   ylphenyl)propyl      Trimethoxyphenyl                                 36  2 0 3-(3-Carboxyphen-                                                                       3-Phenylpropyl                                                                           3,4,5-                                                   yl)propyl            Trimethoxyphenyl                                 37  2 0 3-Hydroxymethyl-                                                                        3-Phenylpropyl                                                                           3,4,5-                                                   phenyl               Trimethoxyphenyl                                 38  2 0 2-Hydroxyphenyl                                                                         3-Phenylpropyl                                                                           3,4,5-                                                                        Trimethoxyphenyl                                 39  2 0 Pyridin-3-yl                                                                            3-Phenylpropyl                                                                           3,4,5-                                                                        Trimethoxyphenyl                                 40  2 0 3-(Thiopen-2-yl)-                                                                       4-Phenylbutyl                                                                            3,4,5-                                                   propyl               Trimethoxyphenyl                                 41  2 0 5-Phenylpentyl                                                                          3-Phenylpropyl                                                                           3,4,5-                                                                        Trimethoxyphenyl                                 42  2 0 3-Allyloxypropyl                                                                        3-Phenylpropyl                                                                           3,4,5-                                                                        Trimethoxyphenyl                                 43  2 0 3-[4-(N,N-                                                                              3-Phenylpropyl                                                                           3,4,5-                                                   Dimethyl-            Trimethoxyphenyl                                         aminecarbonyl)-                                                               phenyl]propyl                                                         44  2 0 3-[4-(Morpholine-                                                                       3-Phenylpropyl                                                                           3,4,5-                                                   4-                   Trimethoxyphenyl                                         carbonyl)phenyl)]-                                                            propyl                                                                45  2 0 4-Allyoxybutyl                                                                          3-Phenylpropyl                                                                           3,4,5-                                                                        Trimethoxyphenyl                                 46  2 0 3-Allyloxyprop-1-                                                                       3-Phenylpropyl                                                                           3,4,5-                                                   ynyl                 Trimethoxyphenyl                                 47  2 0 3-[4-(Piperidine-                                                                       3-phenylpropyl                                                                           3,4,5-                                                   1-                   Trimethoxyphenyl                                         carbonyl)phenyl)-                                                             propyl                                                                48  2 0 5-Allyloxynonyl                                                                         3-Phenylpropyl                                                                           3,4,5-                                                                        Trimethoxyphenyl                                 49  2 0 Methyl    3,5-Bis(benzyl-                                                                          3,4,5-                                                             oxy)phenyl Trimethoxyphenyl                                 50  2 0 2-Allyloxyethyl                                                                         3-Phenylpropyl                                                                           3,4,5-                                                                        Trimethoxyphenyl                                 51  2 0 3-Allyloxy-(E)-                                                                         3-Phenylpropyl                                                                           3,4,5-                                                   prop-l-enyl          Trimethoxyphenyl                                 52  2 0 3-[3-(Morpholine-                                                                       3-Phenylpropyl                                                                           3,4,5-                                                   4-                   Trimethoxyphenyl                                         carbonyl)phenyl]-                                                             propyl                                                                53  2 0 Dec-9-enyl                                                                              3-Phenylpropyl                                                                           3,4,5-                                                                        Trimethoxyphenyl                                 54  2 0 3-[4-(N-Benzyl-                                                                         3-Phenylpropyl                                                                           3,4,5-                                                   aminecarbonyl)-      Trimethoxyphenyl                                         phenyl]propyl                                                         55  2 0 3-[4-(Thiomorpho-                                                                       3-Phenylpropyl                                                                           3,4,5-                                                   line-4-carbonyl)-    Trimethoxyphenyl                                         phenyl)propyl                                                         56  2 0 3-(Morpholine-4-                                                                        3-Phenylpropyl                                                                           3,4,5-                                                   carbonyl)phenyl      Trimethoxyphenyl                                 57  2 0 3-[4-(1-Methyl                                                                          3-Phenylpropyl                                                                           3,4,5-                                                   piperazine-4-        Trimethoxyphenyl                                         carbon-                                                                       yl)phenyl]propyl                                                      58  2 0 3-[4-(1-Benzylpip-                                                                      3-Phenylpropyl                                                                           3,4,5-                                                   erazine-4-carbon-    Trimethoxyphenyl                                         yl)phenyl]propyl                                                      59  2 0 3-[3-(N-Benzyl-                                                                         3-Phenylpropyl                                                                           3,4,5-                                                   aminecarbonyl)-      Trimethoxyphenyl                                         Phenyl]propyl                                                         60  2 0 3-[4-(N-Pyridin-2-                                                                      3-Phenylpropyl                                                                           3,4,5-                                                   ylaminecarbonyl)-    Trimethoxyphenyl                                         phenyl]propyl                                                         61  2 0 Pyridin-3-yl                                                                            3-(Pyridin-3-yl)-                                                                        3,4,5-                                                             propyl     Trimethoxyphenyl                                 62  2 0 Prop-2-enyl                                                                             3,4-Bis-(Pyridin-                                                                        3,4,5-                                                             4-ylmethoxy)phenyl                                                                       Trimethoxyphenyl                                 63  2 0 Pyridin-3-yl                                                                            3-(Pyridin-4-yl-                                                                         3,4,5-                                                             methoxy)phenyl                                                                           Trimethoxyphenyl                                 64  2 0 3-Phenylpropyl                                                                          3-(Pyridin-4-yl-                                                                         3,4,5-                                                             methoxy)phenyl                                                                           Trimethoxyphenyl                                 65  2 0 3-Phenylpropyl                                                                          3,4-Bis-(Pyridin-                                                                        3,4,5 -                                                            4-ylmethoxy)phenyl                                                                       Trimethoxyphenyl                                 66  2 0 Methyl    3,4-Bis-(Pyridin-                                                                        3,4,5-                                                             4-ylmethoxy)phenyl                                                                       Trimethoxyphenyl                                 67  2 0 3-Phenylpropyl                                                                          2,3,4-Tris-                                                                              3,4,5-                                                             (Pyridin-4-                                                                              Trimethoxyphenyl                                                   ylmethoxy)phenyl                                            68  2 0 3-Phenylpropyl                                                                          3-(Morpholine-4-                                                                         3,4,5-                                                             carbonyl)-4-                                                                             Trimethoxyphenyl                                                   (Pyridin-4-                                                                   ylmethoxy)phenyl                                            69  2 0 Methyl    3,4,5-Tris-                                                                              3,4,5-                                                             (Pyridin-4-                                                                              Trimethoxyphenyl                                                   ylmethoxy)phenyl                                            70  2 0 3-Phenylpropyl                                                                          3,4,5-Tris-                                                                              3,4,5-                                                             (Pyridin-4-                                                                              Trimethoxyphenyl                                                   ylmethoxy)phenyl                                            71  2 0 Methyl    3,5-Bis-(Pyridin-                                                                        3,4,5-                                                             4-ylmethoxy)phenyl                                                                       Trimethoxyphenyl                                 72  2 0 3,5-Bis-(Pyridin-                                                                       Methyl     3,4,5-                                                   4-ylmethoxy)phenyl   Trimethoxyphenyl                                 73  2 0 Methyl    3,5-Bis-(Pyridin-                                                                        3,4,5-                                                             4-ylmethoxy)-4-                                                                          Trimethoxyphenyl                                                   methyl-phenyl                                               74  2 0 Ethyl     3,4,5-Tris-                                                                              3,4,5-                                                             (Pyridin-4-                                                                              Trimethoxyphenyl                                                   ylmethoxy)phenyl                                            75  2 0 3,4,5-Tris-                                                                             Ethyl      3,4,5-                                                   (Pyridin-4-          Trimethoxyphenyl                                         ylmethoxy)phenyl                                                      76  2 0 Methyl    3,4,5-Tris-                                                                              3,4,5-                                                             (Pyrazin-2-                                                                              Trimethoxyphenyl                                                   ylmethoxy)phenyl                                            77  2 0 Methyl    3,4,5-Tris-                                                                              3,4-                                                               (Pyridin-4-                                                                              Dimethoxyphenyl                                                    ylmethoxy)phenyl                                            78  2 0 Ethenyl   3,4,5-Tris-                                                                              3,4,5-                                                             (Pyridin-4-                                                                              Trimethoxyphenyl                                                   ylmethoxy)phenyl                                            79  2 0 3,4,5-Tris-                                                                             Ethenyl    3,4,5-                                                   (Pyridin-4-          Trimethoxyphenyl                                         ylmethoxy)phenyl                                                      80  2 0 Propyl    3,4,5-Tris-                                                                              3,4,5-                                                             (Pyridin-4-                                                                              Trimethoxyphenyl                                                   ylmethoxy)phenyl                                            81  2 0 3,4,5-Tris-                                                                             Propyl     3,4,5-                                                   (Pyridin-4-          Trimethoxyphenyl                                         ylmethoxy)phenyl                                                      82  2 0 Methyl    3,4,5-Tris-                                                                              3,4,5-                                                             (Thiophen-3-                                                                             Trimethoxyphenyl                                                   ylmethoxy)phenyl                                            83  2 0 3,4,5-Tris-                                                                             Methyl     3,4,5-                                                   (Thiophen-3-         Trimethoxyphenyl                                         ylmethoxy)phenyl                                                      84  2 0 Methyl    2-Isopropoxy-3,4-                                                                        3,4,5-                                                             Bis-(Pyridin-4-                                                                          Trimethoxyphenyl                                                   ylmethoxy)-phenyl                                           85  2 0 2-Isopropoxy-3,4-                                                                       Methyl     3,4,5-                                                   Bis-(Pyridin-4-      Trimethoxyphenyl                                         ylmethoxy)-phenyl                                                     86  1 0 Methyl    3,4,5-Tris-                                                                              3,4,5-                                                             (Pyridin-4-                                                                              Trimethoxyphenyl                                                   ylmethoxy)phenyl                                            87  1 0 3,4,5-Tris-                                                                             Methyl     3,4,5-                                                   (Pyridin-4-          Trimethoxyphenyl                                         ylmethoxy)phenyl                                                      88  2 0 Methyl    3,4,5-Tris-                                                                              3,4,5-                                                             (Pyridin-4-                                                                              Trimethoxyphenyl                                                   ylmethoxy)phenyl                                            89  2 0 Benzyloxymethyl                                                                         Benzyloxyphenyl                                                                          3,4,5-                                                                        Trimethoxyphenyl                                 90  2 0 Methyl    3,4,5-Tris-                                                                              3,4,5-                                                             (Benzyl-oxy)phenyl                                                                       Trimethoxyphenyl                                 91  2 0 3-Phenylpropyl                                                                          3-(Pyridin-3-yl-                                                                         3,4,5-                                                             carbonyl)phenyl                                                                          Trimethoxyphenyl                                 92  2 0 3-(Pyridin-3-yl-                                                                        3-Phenylpropyl                                                                           3,4,5-                                                   carbonyl)phenyl      Trimethoxyphenyl                                 93  2 0 3-Phenylpropyl                                                                          3-(Pyridin-4-yl-                                                                         3,4-                                                               methoxy)phenyl                                                                           Dimethoxyphenyl                                  94  2 0 3-Phenylpropyl                                                                          3-(Pyridin-4-yl-                                                                         4-Benzyloxy-3,5-                                                   carbonyl)phenyl                                                                          di-methoxyphenyl                                 95  2 0 3-Phenylpropyl                                                                          3-(Pyridin-4-yl-                                                                         4-Allylyoxy-3,5-                                                   carbonyl)phenyl                                                                          di-methoxyphenyl                                 96  2 0 3-Phenylpropyl                                                                          3-(Pyridin-4-yl-                                                                         3-Benzyloxy-4-                                                     carbonyl)phenyl                                                                          methoxyphenyl                                    97  2 0 3-Phenylpropyl                                                                          3-(Pyridin-4-yl-                                                                         3-Allyloxy-4-                                                      carbonyl)phenyl                                                                          methoxyphenyl                                    98  2 0 3-Phenylpropyl                                                                          3-(Pyridin-4-yl-                                                                         3-[3-Phenyl-(E)-                                                   carbonyl)phenyl                                                                          prop-2-enyl]-4-                                                               methoxyphenyl                                    99  2 0 3-Phenylpropyl                                                                          4-(Pyridin-4-yl-                                                                         4-Benzyloxy-3,5-                                                   carbonyl)phenyl                                                                          di-methoxyphenyl                                 100 2 0 3-Phenylpropyl                                                                          4-(Pyridin-4-yl-                                                                         3-Benzyloxy-4-                                                     carbonyl)phenyl                                                                          methoxyphenyl                                    101 2 0 3-Phenylpropyl                                                                          3-(Pyridin-4-yl-                                                                         3,4,5-                                                             carbonyl)phenyl                                                                          Trimethoxyphenyl                                 102 2 0 3-Phenylpropyl                                                                          3-(Pyridin-4-yl-                                                                         3,4-                                                               carbonyl)phenyl                                                                          Dimethoxyphenyl                                  103 2 0 3-Phenylpropyl                                                                          Phenyl     3-Benzyloxy-4-                                                                methoxyphenyl                                    104 2 0 3-Phenylpropyl                                                                          Phenyl     4-Benzyloxy-3,5-                                                              di-methoxyphenyl                                 105 1 0 3-(Pyridin-3-yl)-                                                                       3-Phenylpropyl                                                                           tert-Butyl                                               propyl                                                                106 2 0 3-(Pyridin-3-yl)-                                                                       3-(Pyridin-3-yl)-                                                                        3,4,5-                                                   propyl    propyl     Trimethoxyphenyl                                 107 1 0 Benzyloxymethyl                                                                         Benzyloxyphenyl                                                                          3,4,5-                                                                        Trimethoxyphenyl                                 108 1 0 3-(Pyridin-3-yl)-                                                                       3-(Pyridin-3-yl)-                                                                        3,4,5-                                                   propyl    propyl     Trimethoxyphenyl                                 109 2 0 3-(Pyridin-3-yl)-                                                                       3-(Pyridin-3-yl)-                                                                        Isopropyl                                                propyl    propyl                                                      110 2 0 3-(Pyridin-3-yl)-                                                                       3-(Pyridin-3-yl)-                                                                        Thiophen-2-yl                                            propyl    propyl                                                      111 2 0 3-(Pyridin-3-yl)-                                                                       3-(Pyridin-3-yl)-                                                                        3,4-                                                     propyl    propyl     Methylenedioxy-                                                               phenyl                                           112 2 0 3-(Pyridin-3-yl)-                                                                       3-(Pyridin-3-yl)-                                                                        3,4-                                                     prop-2-ynyl                                                                             prop-2-ynyl                                                                              Methylenedioxy-                                                               phenyl                                           113 2 0 3-(Pyridin-3-yl)-                                                                       3-(Pyridin-3-yl)-                                                                        3,4,5-                                                   prop-2-ynyl                                                                             prop-2-ynyl                                                                              Trimethoxyphenyl                                 114 2 0 3-(Pyridin-2-yl)-                                                                       3-(Pyridin-2-yl)-                                                                        3,4,5-                                                   propyl    propyl     Trimethoxyphenyl                                 115 2 0 Isopropyl 3,4,5-Tris-                                                                              3,4,5-                                                             (Pyridin-4-                                                                              Trimethoxyphenyl                                                   ylmethoxy)phenyl                                            116 2 0 3,4,5-Tris-                                                                             Isopropyl  3,4,5-                                                   (Pyridin-4-          Trimethoxyphenyl                                         ylmethoxy)phenyl                                                      117 2 0 Prop-2-enyl                                                                             3,4,5-Tris-                                                                              3,4,5-                                                             (Pyridin-4-                                                                              Trimethoxyphenyl                                                   ylmethoxy)phenyl                                            118 2 0 3,4,5-Tris-                                                                             Prop-2-enyl                                                                              3,4,5-                                                   (Pyridin-4-          Trimethoxyphenyl                                         ylmethoxy)phenyl                                                      __________________________________________________________________________

The most preferred compounds of this invention are(S)-1-(2-oxo-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxylicacid-4-pyridin-3-yl-1-(3-pyridin-3-yl)propylbutyl ester, and(R)-1-(2-oxo-2-(3,4,5-trimethoxyphenyl)acetyl) piperidine-2-carboxylicacid-4-pyridin-3-yl-1-(3-pyridin-3-yl) propyl)butyl ester,pharmaceutically acceptable derivatives thereof and mixtures thereof.

As used herein, the compounds of this invention, including the compoundsof formula (I), are defined to include pharmaceutically acceptablederivatives thereof. A "pharmaceutically acceptable derivative" denotesany pharmaceutically acceptable salt, ester, or salt of such ester, of acompound of this invention or any other compound which, uponadministration to a patient, is capable of providing (directly orindirectly) a compound of this invention, or a metabolite or residuethereof, characterized by the ability to maintain, increase or restoresensitivity of MDR cells to therapeutic or prophylactic agents or toprevent development of multi-drug resistance. Alternatively, a"pharmaceutically acceptable derivative" denotes any pharmaceuticallyacceptable salt, ester, or salt of such ester, of a compound of thisinvention or any other compound which, upon administration to a patient,is capable of providing (directly or indirectly) a compound of thisinvention, or a metabolite or residue thereof, characterized by theability to prevent, suppress or reduce an immune response.

Compounds of this invention, including those represented by formula (I),may be obtained using any conventional technique. Preferably, thesecompounds are chemically synthesized from readily available startingmaterials, such as alpha-amino acids. Modular and convergent methods forthe synthesis of these compounds are also preferred. In a convergentapproach, for example, large sections of the final product are broughttogether in the final stages of the synthesis, rather than byincremental addition of small pieces to a growing molecular chain.

Scheme 1 illustrates a representative example of a convergent processfor the synthesis of compounds of formula (I'), a preferred subset ofcompounds of formula (I), wherein A is oxygen. The process comprisesesterification of a protected alpha-amino acid of formula (X), wherein Pis a protecting group, with an alcohol of formula (XI). Protectedalpha-amino acids are well known in the art and many are commerciallyavailable. For example, common protecting groups and convenient methodsfor the protection of amino acids are described in T. W. Greene, P. G.M. Wuts, Protective Groups in Organic Chemistry, 2nd Ed., John Wiley andSons, New York (1991). Alkoxycarbonyl groups are preferred forprotection of the nitrogen atom in compounds of formula (X), witht-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), allyloxycarbonyl(Alloc), and trimethylsilylethoxycarbonyl (Teoc) being more preferred.

After esterification, compounds of formula (XII) are deprotected undersuitable deprotection conditions (see Greene, supra), and the free aminogroup of (XIII) is then acylated with a compound of formula (XIV), or anactivated derivative thereof, to yield a compound of formula (I').Methods for activation of carboxyl functionalities in carboxylic acidssuch as compounds of formula (XIV) are well known and many activatingagents are commercially available.

Alcohols of formula (XI) wherein m is 0 (XI') can also be convenientlyprepared, for example, as illustrated in Schemes 2 and 3. Reaction of anorganometallic reagent of formula (XV) and an aldehyde of formula (XVI)provides alcohols of formula (XI') (Scheme 2).

Alternatively (Scheme 3), 1,6-heptadiyn-4-ol can be coupled via ametal-catalyzed reaction to aromatic halides of formula (XVII) to givean alcohol of formula (XVIII). Subsequent hydrogenation provides analcohol of formula (XI"), a preferred subset of alcohols of formula(XI). ##STR5##

Thus, this invention also provides a method for preparing compounds offormula (I') comprising the steps of:

(a) esterifying a protected amino acid of formula (X) with an alcohol offormula (XI) to give an intermediate of formula (XII);

(b) deprotecting the amino protecting group in the intermediate offormula (XII) to give an amino ester of formula (XIII); and

(c) acylating the free amino group in the compound of formula (XIII)with a compound of formula (XIV) or an activated derivative thereof.

It should be appreciated by those of ordinary skill in the art that alarge variety of compounds of formula (I) may be readily prepared,according to the processes illustrated in synthetic Schemes 1, 2 and 3.The same processes may be used for the synthesis of many differentend-products, by altering the variables in the starting materials.

For example, compounds of formula (I") (not shown) wherein A is NH orN--(C1-C4 alkyl) can be synthesized by a peptide coupling reactionbetween a carboxylic acid of formula (X) and an amine of formula (XI'")(not shown) to give an amide of formula (XII'). This step is analogousto the first esterification reaction of Scheme 1. The steps leading from(XII') to (I") are also analogous to those from (XII) to (I') shown inScheme 1.

Optically active compounds of formula (I) may also be prepared usingoptically active starting materials, thus obviating the need forresolution of enantiomers or separation of diastereomers at a late stagein the synthesis.

It will also be appreciated by those of ordinary skill in the art thatthe above synthetic schemes are not intended to comprise a comprehensivelist of all means by which the compounds or the intermediates of thisinvention may be synthesized. Further methods or modifications of theabove general schemes will be evident to those of ordinary skill in theart.

The compounds of this invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and include those which increasebiological penetration into a given biological system (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

According to one embodiment, the compounds of this invention arecharacterized by the ability to increase, restore or maintain thesensitivity of MDR cells to cytotoxic compounds, such as, for example,those typically used in chemotherapy. Based on that ability, thecompounds of this invention are advantageously used as chemosensitizingagents, to increase the effectiveness of chemotherapy in individuals whoare afflicted with drug-resistant cancers, tumors, metastases ordisease. In addition, the compounds of this invention are capable ofmaintaining sensitivity to therapeutic or prophylactic agents innon-resistant cells. Therefore, the compounds of this invention areuseful in treating or preventing multi-drug resistance in a patient.

As used throughout this application, the term "patient" refers tomammals, including humans. And the term "cell" refers to mammaliancells, including human cells.

As used herein, the terms "sensitizing agent", "sensitizer","chemosensitizing agent", "chemosensitizer" and "MDR modifier" denote acompound having the ability to increase or restore the sensitivity of anMDR cell, or to maintain the sensitivity of a non-resistant cell, to oneor more therapeutic or prophylactic agents. The term "MDR sensitization"and "sensitization" and "resensitization" refer to the action of such acompound in maintaining, increasing, or restoring drug sensitivity.

According to one embodiment of this invention, compounds of thisinvention that are useful in increasing, restoring or maintaining drugsensitivity are also capable of binding to the protein FKBP-12 or otherrelated FK-506 binding proteins such as FKBP-13, FKBP-26 and FKBP-52. Invitro tests (data not shown) of these compounds demonstrate that theagents bind to FKBP-12. Thus, this invention also comprises a class ofchemosensitizing agents other than FK-506, characterized by the abilityto bind to the FK binding protein-12 or related FK binding proteins,pharmaceutical compositions including such agents and a physiologicallyacceptable adjuvant, carrier or vehicle, and methods of using thosecompositions for treating or preventing multi-drug resistance in apatient.

According to another embodiment, the compounds of this invention canalso be used as immunosuppressants for treatment or prophylaxis of organrejection or treatment of chronic graft rejection and for the treatmentor prevention of autoimmune diseases.

For example, the immunosuppressive compounds of this invention can beperiodically administered to a patient undergoing bone marrow or organtransplantation or for another reason in which it is desirable toprevent, reduce substantially or suppress a patient's immune response,such as in various autoimmune diseases. The compounds of this inventioncan also be administered to mammals other than humans for prevention ortreatment of various mammalian autoimmune diseases.

The novel compounds of the present invention possess a high degree ofactivity in suppression of antigen-stimulated growth and clonalexpansion of T-cells, especially those T-cells characterized as "helper"T-cells. This activity is useful in the primary prevention of organtransplant rejection, in the rescue of transplanted organs during arejection episode, and in the treatment of any of several autoimmunediseases known to be associated with inappropriate autoimmune responses.These autoimmune diseases include: uveitis, Behcet's disease, Grave'sophthalmopathy, psoriasis, acute dermatomyositis, atopic skin disease,scleroderma, eczema, pure red cell aplasia, aplastic anemia, primarycirrhosis, autoimmune hepatitis, ulcerative colitis, Crohn's disease,amyotrophic lateral sclerosis, myasthenia gravis, multiple sclerosis,nephrotic syndrome, membrano-proliferative glomerulonephritis,rheumatoid arthritis and insulin-dependent diabetes mellitus. In all ofthe above-listed autoimmune diseases, treatment is effective to reducethe symptoms and slow progression of the disease. In the case ofinsulin-dependent diabetes mellitus, treatment as described below ismost effective when instituted before the complete cessation of naturalinsulin production and transition to complete dependence on externalinsulin.

Because compounds according to this invention exhibit immunosuppressiveactivity, as well as activity against multi-drug resistance, it will beappreciated by those of ordinary skill in the art that compoundspreferred for use in preventing or modulating multi-drug resistance arethose which are not significantly immunosuppressive at clinically usefulor prophylactically or therapeutically active levels--i.e., the effect,if any, of immunosuppression of a given patient does not outweigh thevalue of sensitization activity of the compound to that patient. Thoseof ordinary skill in the art will also appreciate that suchimmunosuppressive capabilities can be ascertained by the in vitro assaysset forth below or as described in U.S. patent application Ser. No.07/547,814 (now U.S. Pat. No. 5,192,773), the disclosure of which isincorporated herewith.

The compounds of the present invention may be used in the form ofpharmaceutically acceptable salts derived from inorganic or organicacids and bases. Included among such acid salts are the following:acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate,bisulfate, butyrate, citrate, camphorate, camphorsulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate,hexanoate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate,2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate,persulfate, 3-phenyl-propionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate and undecanoate. Base saltsinclude ammonium salts, alkali metal salts, such as sodium and potassiumsalts, alkaline earth metal salts, such as calcium and magnesium salts,salts with organic bases, such as dicyclohexylamine salts,N-methyl-D-glucamine, and salts with amino acids such as arginine,lysine, and so forth. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides and iodides; dialkylsulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides, such as benzyl and phenethylbromides and others. Water or oil-soluble or dispersible products arethereby obtained.

The compounds of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir in dosage formulationscontaining conventional non-toxic pharmaceutically-acceptable carriers,adjuvants and vehicles. The term "parenteral" as used herein includessubcutaneous, intravenous, intramuscular, intra-articular,intrasynovial, intrasternal, intrathecal, intrahepatic, intralesionaland intracranial injection or infusion techniques.

The pharmaceutical compositions of this invention comprise any of thecompounds of the present invention, or pharmaceutically acceptable saltsthereof, with any pharmaceutically acceptable carrier, adjuvant orvehicle. Pharmaceutically acceptable carriers, adjuvants and vehiclesthat may be used in the pharmaceutical compositions of this inventioninclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, potassium sorbate,partial glyceride mixtures of saturated vegetable fatty acids, water,salts or electrolytes, such as protamine sulfate, disodium hydrogenphosphate, potassium hydrogen phosphate, sodium chloride, zinc salts,colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

According to this invention, the pharmaceutical compositions may be inthe form of a sterile injectable preparation, for example a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to techniques known in the art using suitabledispersing or wetting agents and suspending agents. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solutionand isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose, any bland fixed oil may be employed including synthetic mono-or di-glycerides. Fatty acids, such as oleic acid and its glyceridederivatives are useful in the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions may also contain a long-chain alcohol diluent or dispersant,such as Ph. Helv or similar alcohol.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers which are commonly used includelactose and corn starch. Lubricating agents, such as magnesium stearate,are also typically added. For oral administration in a capsule form,useful diluents include lactose and dried corn starch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions of this invention may beadministered in the form of suppositories for rectal administration.These can be prepared by mixing the agent with a suitable non-irritatingexcipient which is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical compositions can be formulatedin a suitable lotion or cream containing the active components suspendedor dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith our without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated, the particular mode of administration and the intendedeffect of therapy, i.e., immunosuppression or treatment or prevention ofmulti-drug resistance. It should be understood, however, that a specificdosage and treatment regimen for any particular patient will depend upona variety of factors, including the activity of the specific compoundemployed, the age, body weight, general health, sex, diet, time ofadministration, rate of excretion, drug combination, and the judgment ofthe treating physician and the severity of the particular disease beingtreated. The amount of active ingredient may also depend upon thetherapeutic or prophylactic agent, if any, with which the ingredient isco-administered.

According to those embodiments of this invention directed to thetreatment or prevention of multi-drug resistance, the term"pharmaceutically effective amount" refers to an amount effective toprevent multi-drug resistance or maintain, increase or restore drugsensitivity in MDR cells. According to those embodiments of thisinvention directed to immunosuppression, rather than treatment orprevention of multi-drug resistance, the term "pharmaceuticallyeffective amount" refers to an amount effective to prevent, suppress orsubstantially reduce the immune response of a mammal.

Dosage levels of between about 0.01 and about 100 mg/kg body weight perday, preferably between about 0.5 and about 50 mg/kg body weight per dayof the active ingredient compound are useful. A typical preparation willcontain between about 5% and about 95% active compound (w/w).Preferably, such preparations contain between about 20% and about 80%active compound. Generally speaking, within the dosage ranges specifiedherein, the preferred compounds of this invention induceMDR-sensitization at doses which are not substantially immunosuppressiveto the patient.

When the compounds of this invention are administered in combinationtherapies with other agents, they may be administered sequentially orconcurrently to the patient. Alternatively, pharmaceutical orprophylactic compositions according to this invention may comprise acombination of a compound of this invention and another therapeutic orprophylactic agent.

For example, the compounds may be administered either alone or incombination with one or more therapeutic agents, such aschemotherapeutic agents, (e.g., actinomycin D, doxorubicin, vincristine,vinblastine, etoposide, amsacrine, mitoxantrone, tenipaside, taxol andcolchicine) and/or a chemosensitizing agent (e.g., cyclosporin A andanalogs, phenothiazines and thioxanthenes), in order to increase thesusceptibility of the MDR cells within the patient to the agent oragents.

Alternatively, when the target use of the compounds of this invention isimmunosuppression, rather than treatment or prevention of multi-drugresistance, the compounds may be administered in combination withasteroid, such as methyl prednisalone acetate, for additionalimmunosuppressive effect. The steroid is administered orally,intravenously, rectally, topically or by inhalation. Dosages (based uponmethyl prednisalone acetate) of 0.1-5 mg/kg/day may be employed. Aninitial loading dose of 100-500 mg may be employed. Steroid doses may bedecreased with time from the higher toward the lower doses as theclinical situation indicates.

The compounds can be administered with other immunosuppressant drugs,such as rapamycin, azathioprine, 15-deoxyspergualin, mycophenolic acid,brequinar, cyclosporin A, FK-506 or combinations of these, to increasethe immunosuppressive effect. Administration of cyclosporin and FK-506together should be avoided due to contraindications reported resultingfrom coadministration of these immunosuppressants. The dosage level ofother immunosuppressant drugs will depend upon the factors previouslystated and the immunosuppressive effectiveness of the drug combination.

OKT3, which is a murine monoclonal antibody to CD3 surface antigen ofhuman T lymphocytes, can also be coadministered intravenously withcompounds of the present invention for rescue and reversal of acuteallograft rejections, particularly in renal transplantations.

In order that this invention may be more fully understood, the followingexamples are set forth. These examples are for the purpose ofillustration only and are not to be construed as limiting the scope ofthe invention in any way.

EXAMPLES

General Methods

Proton nuclear magnetic resonance (¹ H NMR) spectra were recorded at 500MHz on a Bruker AMX 500. Chemical shifts are reported in parts permillion (δ) relative to Me₄ Si (δ 0.0). Analytical high performanceliquid chromatography was performed on either a Waters 600E or a HewlettPackard 1050 liquid chromatograph.

Example 1 Synthesis of (S)-1,7-Diphenyl-4-heptanylN-(3,4,5-trimethoxyphenylglyoxyl)pipecolate (3)

4-Phenyl-1-butanal (119). To a solution of 3.2 mL (20.8 mmol) of4-phenyl-1-butanol (Aldrich Chemical Co.) in 20 mL of CH₂ Cl₂ at 0° C.was added 3.2 g of powdered 3 Å molecular sieves and then 5.37 g (24.9mmol) of pyridinum chlorochromate (PCC). The resulting suspension wasstirred at 0° C. for 1 h at which time an additional 2.16 g (10.0 mmol)of PCC was added and the reaction mixture was warmed to roomtemperature. After stirring at ambient temperature for 0.5 h, thereaction mixture was diluted with ether and filtered through celite togive 2.5 g of the crude product. Flash chromatography (elution with 5%ethyl acetate in hexane) yielded 700 mg of the aldehyde 119. ¹ H NMR wasconsistent with the structure.

3-Phenyl-1-propylmagnesium bromide (120). To a suspension of 736 mg(30.3 mmol) of magnesium turnings in 50 mL of THF at room temperaturewas added 50 μL of 1,2-dibromoethane followed by the dropwise additionof 5.5 g (25.1 mmol) of 1-bromo-3-phenylpropane (Aldrich Chemical Co.).After stirring at room temperature for 0.5 h, the supernatant wastransferred via cannula to a 100 mL storage vessel and subsequently usedas a 0.5M THF solution of the Grignard reagent 120.

1,7-Diphenyl-4-heptanol (121). To a solution of 700 mg (4.7 mmol) of4-phenyl-1-butanal (119) in 5.0 mL of THF at 0° C. was added 10.0 mL(5.0 mmol) of 3-phenyl-1-propylmagnesium bromide (120) and the resultingmixture was stirred at 0° C. for 0.5 h. The mixture was then quenched bythe dropwise addition of saturated NH₄ Cl and diluted with ether. Thephases were separated and the organic layer was washed with water andbrine and then dried over MgSO₄. Concentration gave 1.12 g of thealcohol 121 as an oil. ¹ H NMR spectrum was consistent with thestructure.

(S)-Boc-1-Pipecolyl-1,7-diphenyl-4-heptanyl ester (122). To a solutionof 164 mg (0.72 mmol) of Boc-L-Pipecolic acid in 5.0 mL of CH₂ Cl₂ atroom temperature was added 174 mg (0.65 mmol) of alcohol 121, 140 mg(0.72 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDC) and a catalytic amount of N,N-dimethylaminopyridine(DMAP). The reaction mixture was stirred at ambient temperature for 0.5h and then applied directly to a silica gel column. Elution with 10%ethyl acetate in hexane afforded 76.2 mg of the ester 122 as an oil. ¹ HNMR spectrum was consistent with the structure.

(S)-1,7-Diphenyl-4-heptanylpipecolate (123). To a solution of 47 mg(0.10 mmol) of the ester 122 in 1.0 mL of CH₂ Cl₂ at ambient temperaturewas added 1.0 mL of trifluoroacetic acid. After stirring at roomtemperature for 0.5 h, the resulting solution was neutralized by thedropwise addition of saturated K₂ CO₃. The layers were separated and theorganic phase was washed with water, dried over MgSO₄ and concentratedto yield 23 mg of the amine 123 as an oil. ¹ H NMR consistent withstructure.

3,4,5-Trimethoxybenzoylformic acid (124). To a solution of 9.2 g (43.4mmol) of 3,4,5-trimethoxyacetophenone (Aldrich Chemical Co.) in 35 mL ofpyridine was added 6.3 g (56.7 mmol) of selenium dioxide and theresulting solution was heated at reflux overnight. The reaction mixturewas cooled to room temperature, filtered through celite and concentratedto yield a dark brown oil which was dissolved into ethyl acetate andwashed with 1.0N HCl and then with saturated NaHCO₃. The basic aqueouslayer was diluted with ether and acidified with concentrated HCl. Thelayers were separated and the organic phase was washed with brine andthen dried over Na₂ SO₄ to give 8.4 g of the acid 124 as a dark yellowsolid. Recrystallization of this material from ethyl acetate-hexane thengave 6.8 g of the acid 124 as a pale yellow solid. ¹ H NMR consistentwith structure.

(S)-1,7-Diphenyl-4-heptanyl N-(3,4,5-trimethoxyphenylglyoxyl)pipecolate(3). To a solution of 23 mg (0.06 mmol) of the amine 123 in 1.0 mL ofCH₂ Cl₂ at room temperature was added 21.8 mg (0.09 mmol) of the acid124 and then 17.9 mg (0.09 mmol) of EDC and the resulting solution wasstirred at room temperature for 0.5 h and applied directly to a silicagel column. Elution with 15% ethyl acetate in hexane gave 8.4 mg of theamide 3 as a mixture of rotamers. ¹ H NMR (500 MHz CDCl₃ δ 7.35-7.06(m), 5.32 (br s), 5.00 (br s), 4.88 (br s), 4.58 (d), 4.31 (br s), 3.95(s), 3.90 (s), 3.89 (s), 3.85 (s), 3.44 (d), 3.21 (t), 3.04 (t), 2.54(br s), 2.51 (br s), 2.42 (br s), 2.30 (d), 2.15 (d), 1.83-1.21 (m).##STR6##

Example 2 Synthesis of (R and S)-1-(3-Phenoxy)phenyl-4-phenyl-1-butyl(S)-N-(3,4,5-trimethoxyphenylglyoxyl)pipecolate 4).

3-Phenoxybenzaldehyde (125). To a solution of 1.8 mL (10.3 mmol) of3-phenoxybenzyl alcohol (Aldrich Chemical Co.) in 20 mL of CH₂ Cl₂ atroom temperature was added 1.5 g of powdered 4 Å molecular sieves and2.5 g of activated MnO₂. The resulting suspension was stirred at roomtemperature for 0.5 h, at which time an additional 2.5 g of MnO₂ wasadded. After stirring at room temperature for 0.5 h the reaction mixturewas filtered through celite to give 1.84 g of the aldehyde 125 as anoil. ¹ H NMR consistent with structure.

(R and S)-1-(3-Phenoxy)phenyl-4-phenyl-1-butanol (126). The alcohol 126was prepared from 190 mg (0.96 mmol) of aldehyde 125 and 2.0 mL (1.0mmol) of the Grignard reagent 120 in 2.0 mL of THF as described abovefor the synthesis of the alcohol 121 in Example 1. Flash chromatography(elution with 10% ethyl acetate in hexane) afforded 108 mg of theracemic alcohol 126. ¹ H NMR consistent with structure.

(S)-N-3,4,5-(Trimethoxyphenyl)glyoxyl pipecolic acid (127). To a slurryof 953.3 mg (3.4 mmol) of the tartrate salt of (S)-pipecolic acid(Egbertson, M. and Danishefsky, S. J., J. Org. Chem. 1989, 54, 11) in7.0 mL of CH₂ Cl₂ at 0° C. was added 3.9 mL (22.39 mmol) ofdiisopropylethylamine and 2.4 mL (18.9 mmol) of chlorotrimethylsilaneand the resulting solution was allowed to stir at 0° C. for 0.5 h. In aseparate reaction flask 450 μL (5.2 mmol) of oxalyl chloride and threedrops of DMF were added to a solution of 820 mg (3.4 mmol) of acid 124in 7.0 mL of CH₂ Cl₂. After the evolution of gas ceased, the entirecontents of the second flask were added to the first reaction vessel andthe resulting mixture was allowed to stir at room temperature for 1 h.The reaction mixture was concentrated, dissolved into ether and washedwith 0.5N HCl and then saturated NaHCO₃. The basic aqueous phase wasacidified with concentrated HCl and extracted with ether. The etherealextracts were washed with water, brine, dried over MgSO₄ andconcentrated to give 490 mg of the acid 127. ¹ H NMR consistent withstructure.

(R and S)-1-(3-Phenoxy)phenyl-4-phenyl-1-butyl(S)-N-(3,4,5-trimethoxyphenylglyoxyl)pipecolate (4). To a solution of29.4 mg (0.08 mmol) of acid 127 in 2.0 mL of CH₂ Cl₂ at room temperaturewas added 11 μL (0.13 mmol) of oxalyl chloride and three drops of DMFand the reaction mixture was allowed to stir at room temperature for 0.5h and was then concentrated and suspended in 1.0 mL of benzene. To thissuspension was added 32.0 mg (0.1 mmol) of alcohol 126 and 13.4 mg (0.1mmol) of silver cyanide. The resulting mixture was heated at refluxovernight, cooled to room temperature and concentrated. Flashchromatography (elution with 10% ethyl acetate in hexane) gave 8.8 mg ofthe ester 4 as a mixture of diastereomers. ¹ H NMR (500 MHz CDCl₃)δ7.34-7.19 (m), 7.18-7.03 (m) 7.02-6.84 (m), 6.83-6.72 (m), 5.73 (q),5.69-5.55 (m), 5.38 (t), 4.55 (br d), 4.35 (dd), 3.94 (s), 3.92 (s),3.89 (s), 3.83 (s), 3.73 (s), 3.63 (s), 3.48-3.35 (m), 3.20 (t), 3.10(t), 2.60 (q), 2.40 (dd), 1.95-1.91 (m), 1.90-1.45 (m). ##STR7##

Example 3 Synthesis of (R and S)-6-Phenyl-1-(3-pyridyl)-3-hexyl(S)-N-(3,4,5-trimethoxyphenylglyoxyl)pipecolate (7).

3-(3-Pyridyl)-1-propylaldehyde (128). To a solution of 2.3 g (5.46 mmol)of the Dess-Martin periodinane (Dess, D. B.; Martin, J. C. J. Org. Chem.1983, 48, 4155) in 10 mL of CH₂ Cl₂ at 0° C. was added 470 μL (3.65mmol) of 3-(3-pyridyl)-1-propanol and the resulting mixture was allowedto warm from 0° C. to ambient temperature over a 1.5 h period. To thissolution was added 6.0 g (38.22 mmol) of Na₂ S₂ O₃ in saturated NaHCO₃and the reaction mixture was allowed to stir at room temperature for 15min. The reaction was extracted with CH₂ Cl₂, dried over MgSO₄ andconcentrated. Flash chromatography (elution with 3:1 hexane;acetone)yielded the product aldehyde 128 as an oil. ¹ H NMR consistent withstructure.

(R and S)-6-phenyl-1-(3-pyridyl)-3-hexanol (129). The alcohol 129 wasprepared from 125 mg (0.92 mmol) of aldehyde 128 and 2.0 mL (1.0 mmol)of 120 in 2.0 mL of THF as described above for the synthesis of alcohol121 in Example 1 to give 221 mg of the crude alcohol 129. ¹ H NMRconsistent with structure.

(S)-Boc-Pipecolyl-(R and S)-6-Phenyl-1-(3-pyridyl)-3-hexyl ester (130).The ester 130 was prepared from 125 mg (0.49 mmol) of alcohol 129, 93 mg(0.41 mmol) of Boc-pipecolic acid, 94 mg (0.49 mmol) of EDC and acatalytic amount of DMAP in 1.0 mL of CH₂ Cl₂ and 1.0 mL of DMF asdescribed above for the synthesis of 122 in Example 1. Flashchromatography (elution with 2:1 hexane: ethyl acetate) gave 105 mg ofthe diastereomeric ester 130 as an oil. ¹ H NMR consistent withstructure.

(R and S)-6-Phenyl-1-(3-pyridyl)-3-hexyl (S)-pipecolate (131). The amine131 was synthesized by treating 95 mg (0.20 mmol) of the ester 130 with1.0 mL of trifluoroacetic acid in 3.0 mL of CH₂ Cl₂ as described abovefor the preparation of amine 123 in Example 1, giving 58 mg of thediastereomeric amine 131 as an oil. ¹ H NMR consistent with structure.

(R and S)-6-Phenyl-1-(3-pyridyl)-3-hexyl(S)-N-(3,4,5-trimethoxyphenylglyoxyl)pipecolate (7). The ester 7 wasprepared from 54 mg (0.15 mmol) of the amines 131, 50 mg (0.22 mmol) ofthe acid 124 and 42 mg (0.22 mmol) of EDC in 3.0 mL of CH₂ Cl₂ asdescribed above in the synthesis of ester 3 in Example 1. Flashchromatography (elution with 1:1 ethyl acetate :hexane) gave 73 mg ofthe diasteromeric ester 7 as a mixture of rotamers. ¹ H NMR (500 MHzCDCl₃) δ 8.48-8.42 (m), 7.50-7.41 (m), 7.32 (d), 7.27-7.03 (m), 5.38(d), 5.31 (d), 5.06-5.01 (m), 4.97-4.93 (m), 4.60 (br d), 3.92 (s), 3.88(s), 3.86 (s), 3.84 (s), 3.82 (s), 3.79 (s), 3.46 (br d), 3.27 (br t),2.73-2.68 (m), 2.38-2.29 (m), 1.98-1.76 (m), 1.75-1.60 (m), 1.56-1.51(m), 1.38-1.21 (m). ##STR8##

Example 4 Synthesis of (R andS)-(E)-1-[trans-(4-Hydroxycyclohexyl)]-2-methyl-6-phenyl-3-hex-1-enyl(S)-N-(3,4,5-trimethoxyphenylglyoxyl)pipecolate (8).

cis-and trans-4-(tert-Butyldimethylsilyloxy)cyclohexan-1-ol (132) and(133). To a solution of 3.43 g (21.7 mmol) of cis- and trans-methyl4-hydroxycyclohexane carboxylate (Noyce, D. S.; Denney, D. B. J. Am.Chem. Soc. Vol. 74, 5912 (1952)) in 45 mL of methylene chloride at 0° C.was added 3.0 mL (26.0 mmol) of 2,6-lutidine followed by 5.5 mL (23.0mmol) of tert-butyldimethylsilyl trifluoromethanesulfonate. The ice bathwas removed and the reaction mixture was allowed to stir at 25° C. for 2h, at which time the solution was poured into saturated sodiumbicarbonate. The layers were partitioned and the organic layer waswashed with saturated copper sulfate and water and then dried over MgSO₄to give 5.9 g of the crude methyl esters. A solution of 5.72 g (21.0mmol) of this mixture in 45 mL of anhydrous THF was treated with 400 mg(10.5 mmol) of lithium aluminum hydride. The reaction mixture wasstirred at 25° C. for 0.5 h and was then quenched by the slow additionof a saturated solution of Rochelle's salt. The mixture was diluted withether, the layers were partitioned and the aqueous layer was washedtwice with ethyl acetate. The combined organic extracts were dried overMgSO₄ and concentrated to give 4.9 g of the diastereomeric alcohols.Flash chromatography (elution with 1:5 ethyl acetate-hexane) gave 650 mgof 132, 1.10 g of 133 and 2.40 g of a mixture of the two. Data for 132:¹ H NMR (300 MHz, CDCl₃) δ 3.99-3.92 (m), 3.46 (d), 1.72-1.58 (m),1.57-1.36 (m), 0.86 (s), 0.08 (s). Data for 133: ¹ H NMR (300 MHz,CDCl₃) δ 3.47 (dddd), 3.38 (d), 1.86-1.67 (m), 1.47-1.16 (m), 1.05-0.77(m), 0.72 (s), 0.02 (s).

(E)-Ethyl3-[trans-(4-tert-Butyldimethylsilyloxycyclohexyl)]-2-methylprop-2-enoate(134). To a -78° C. solution of oxalyl chloride (785 μL, 9.0 mmol) in 10mL of methylene chloride was added dimethylsulfoxide (1.3 mL, 18.0mmol). The resulting solution was stirred for 5 min and then 1.1 g (4.5mmol) of the alcohol 133 was added in 10 mL of methylene chloride. Thereaction mixture was stirred at -78° C. for 45 min at which time 3.8 mL(27.0 mmol) of triethylamine was added and the solution was allowed towarm to ambient temperature. The reaction was quenched with 1.0N HCl andthe aqueous layer was extracted with three portions of methylenechloride. The combined organic extracts were dried over MgSO₄ andevaporated to dryness to give 1.0 g of the intermediate aldehyde. Asolution of this aldehyde (450 mg, 1.86 mmol) was treated directly with710 mg (1.95 mmol) of (carbethoxyethylidene)triphenyl-phosphorane in 5.0mL of methylene chloride. The resulting reaction mixture was stirred atambient temperature overnight and was then poured into water. The layerswere partitioned and the aqueous layer was extracted twice withmethylene chloride. The combined organic layers were dried over MgSO₄and concentrated to yield the enoate 134 containing a minor amount ofthe Z isomer. ¹ H NMR consistent with structure.

(E)-3-[trans-(4-tert-Butyldimethylsilyloxycyclohexyl)]-2-methylprop-2-en-1-ol(135). To a solution of 860 mg (2.6 mmol) of enoate 134 in 5.0 mL ofanhydrous tetrahydrofuran at 25° C. was added 50 mg (1.3 mmol) oflithium aluminum hydride and the resulting mixture was allowed to stirfor 30 min. The reaction was quenched by the slow addition of saturatedRochelle's salt and diluted with ethyl acetate. The layers wereseparated and the aqueous layer was extracted with two portions of ethylacetate. The combined organic extracts were washed with both water andbrine and then dried over MgSO₄. Evaporation and flash chromatography(elution with 15% ethyl acetate in hexane) gave 370 mg of the allylicalcohol 135. ¹ H NMR consistent with structure.

(E)-3-[trans-(4-tert-Butyldimethylsilyloxycyclohexyl)]-2-methylprop-2-en-1-al(136). To a -78° C. solution of oxalyl chloride (105 μL, 1.2 mmol) in1.0 mL of methylene chloride was added dimethylsulfoxide (170 μL, 2.4mmol). The resulting solution was stirred for 5 min and then 170 mg (0.6mmol) of the alcohol 135 was added in 1.0 mL of methylene chloride. Thereaction mixture was stirred at -78° C. for 45 min at which time 500 μL(3.6 mmol) of triethylamine was added and the solution was allowed towarm to ambient temperature, The reaction was quenched with 1.0N HCl andthe aqueous layer was extracted with three portions of methylenechloride. The combined organic extracts were dried over MgSO₄ andevaporated to dryness to give the crude aldehyde 136 which was useddirectly in the next reaction. ¹ H NMR consistent with structure,

(R andS)-(E)-1-[trans-(4-tert-Butyldimethylsilyloxycyclohexyl)]-2-methyl-6-phenylhex-1-en-3-ol(137). The alcohol 137 was prepared from the crude aldehyde 136 and 1.5mL (0.75 mmol) of 120 in 2.0 mL of THF as described above for thesynthesis of alcohol 121 in Example 1 to give 220 mg of the crudediastereomeric alcohol 137. Flash chromatography (elution with 20% ethylacetate in hexane) afforded 146 mg of the alcohol 137 as an oil. ¹ H NMRconsistent with structure.

(R andS)-(E)-1-[trans-(4-tert-Butyldimethylsilyloxycyclohexyl)]-2-methyl-6-phenyl-3-hex-1-enyl(S)-N-(3,4,5-trimethoxyphenylglyoxyl)pipecolate (138). To a solution of75.7 mg (0.22 mmol) of acid 127 in 2.5 mL of CH₂ Cl₂ at room temperaturewas added 30 μL (0.34 mmol) of oxalyl chloride and three drops of DMFand the reaction mixture was allowed to stir at room temperature for 0.5h and was then concentrated and suspended in 1.0 mL of benzene. To thissuspension was added 43.4 mg (0.11 mmol) of alcohol 137 and 28.8 mg(0.22 mmol) of silver cyanide. The resulting mixture was heated atreflux overnight, cooled to room temperature and concentrated. Flashchromatography (elution with 4% acetone in hexane) gave 17.5 mg of theester 138 as a mixture of diastereomers. ¹ H NMR consistent withstructure.

(R andS)-(E)-1-[trans-(4-Hydroxycyclohexyl)]-2-methyl-6-phenyl-3-hex-1-enyl(S)-N-(3,4,5-trimethoxyphenylglyoxyl)pipecolate (8). To a solution of17.5 mg (0.02 mmol) of the ester 138 in 1.0 mL of CH₃ CN at roomtemperature was added 10 drops of a 95:5 solution of CH₃ CN:5% HF andthe resulting mixture was stirred at room temperature for 0.5 h. Thereaction mixture was neutralized with saturated K₂ CO₃ and extractedinto ether. The ether layers were washed with water, dried over MgSO₄and concentrated to yield 7.2 mg of crude material. Flash chromatography(elution with 15% acetone in hexane) gave 4.9 mg of the diastereomericalcohol 8 as a mixture of rotamers. ¹ H NMR (500 MHZ, CDCl₃) δ 7.38-7.02(m), 5.35-5.01 (m), 4.62-4.53 (m), 4.28 (t), 3.95 (s), 3.89 (s), 3.87(s), 3.86 (s), 3.85 (s), 3.81 (s), 3.55 (m), 3.45 (m), 3.20 (m),3.10-2.90 (m), 2.60-2.45 (m), 2.32 (t), 2.10 (t), 1.95(d), 1.85-1.40(m), 1.39-1.02 (m). ##STR9##

Example 5 Synthesis of (R and S)-5-(3-indolyl)-1-phenyl-2-pentyl(S)-N-(3,4,5-tri-methoxyphenylglyoxyl)pipecolate (11).

N-Methyl-N-Methoxy-4-(3-indolyl)butyramide (139). To a slurry of 1.75 g(8.61 mmol) of 3-indolebutyric acid (Aldrich Chemical Co.) inacetonitrile at room temperature was added 7.0 mL (40.2 mmol) ofN,N-diisopropylethylamine, 1.0 g (10.3 mmol) ofN,N-dimethylhydroxylamine hydrochloride and 4.19 g (9.5 mmol) ofbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP reagent) and the resulting mixture was allowed to stir at roomtemperature overnight and was then concentrated to dryness. The residuewas dissolved into ethyl acetate and washed with water, 0.5N HCl,saturated NaHCO₃ and brine and then dried over MgSO₄ and concentrated.Flash chromatography (elution with a gradient of 2-10% ether inmethylene chloride) provided 2.0 g of the amide 139. ¹ H NMR consistentwith structure.

Benzyl-3-(3-indolyl)propyl ketone (1.40). To a solution of 147 mg (0.60mmol) of amide 139 in 4.0 mL of THF at -78° C. was added 1.31 mL (1.31mmol) of benzylmagnesium chloride (1.0M in Et₂ O) and the reactionmixture was allowed to warm to room temperature and stir for 3 h. Thereaction was quenched with 5% KHS₄ and extracted into ether. Thecombined ethereal layers were washed with brine and dried over MgSO₄.Flash chromatography (elution with 25% ether in hexane) gave 108 mg ofthe ketone 140. ¹ H NMR consistent with structure.

(R and S)-5-(3-indolyl)-1-phenyl-2-pentanol (141). To a slurry of 105 mg(0.38 mmol) of ketone 140 in 3.0 mL of MeOH at 0° C. was added 30 mg(0.79 mmol) of solid NaBH₄ and the resulting suspension was allowed tostir for 3 h. The reaction mixture was quenched with 5% KHSO₄ andextracted into ethyl acetate. The combined organic extracts were washedwith brine and dried over MgSO₄. Flash chromatography (elution with 4%ether in methylene chloride) gave 81 mg of the alcohol 141 as a whitesolid. ¹ H NMR consistent with structure.

(S)-Boc-Pipecolyl-(R and S)-5-(3-indolyl)-1-phenyl-2-pentyl ester (142).The ester 142 was prepared from 80 mg (0.29 mmol) of alcohol 141, 82 mg(0.36 mmol) of (S)-Boc-pipecolic acid, 66 mg (0.34 mmol) of EDC and acatalytic amount of 4-pyrrolidinopyridine in 2.0 mL of CH₂ Cl₂ (mixturewas allowed to stir overnight at room temperature) as described abovefor the synthesis of ester 122 in Example 1. Flash chromatography(elution with 4:10:26 ether: methylene chloride: hexane) gave 108 mg ofthe diastereomeric ester 142 as a white foam. ¹ H NMR consistent withstructure.

(R and S)-5-(3-indolyl)-1-phenyl-2-pentyl (S)-pipecolate hydrochloridesalt (143). Anhydrous HCl was bubbled into a solution of 103 mg (0.21mmol) of the ester 142 in 10 mL of EtOAc at -20° C. for 10 min and thenthe reaction mixture was purged with N₂. Concentration gave 108 mg ofthe crude amine 143 as the hydrochloride salt. ¹ H NMR consistent withstructure.

(R and S)-5-(3-indolyl)-1-phenyl-2-pentyl(S)-N-(3,4,5-trimethoxyphenylglyoxyl)pipecolate (11). To a slurry of 108mg of the crude amino hydrochloride 143 in CH₃ CN at room temperaturewas added 91 μL (0.52 mmol) of N,N-diisopropylethylamine, 76 mg (0.31mmol) of acid 124, and 111 mg (0.25 mmol) of the BOP reagent and theresulting mixture was stirred at room temperature for two days and thenwas concentrated to dryness. The residue was reconstituted into 75 mL ofethyl acetate and then sequentially washed with water, 5% KHSO₄,saturated NaHCO₃ and brine and then dried over MgSO₄ and concentrated.Flash chromatography (elution with 4% ether in methylene chloride) gave56.7 mg of the diastereomeric amide 11 as a rotameric mixture. ¹ H NMR(500 MHz, CDCl₃) δ 7.98 (d), 7.56 (t), 7.38-6.73 (m), 5.38-5.14 (m),3.90 (m), 3.38 (brt), 3.10 (brt), 2.97-2.60 (m), 2.31 (d), 2.10 (d),1.98-1.17 (m), 0.8 (m). R_(f) 0.51 (10% ether in methylene chloride).##STR10##

Example 6 Synthesis of (R and S)-2-Benzyl-4-phenyl-1-butyl(S)-N-(3,4,5-trimethoxyphenylglyoxyl)pipecolate (16).

(R and S)-2-Benzyl-4-phenyl-1-butyric acid (144). To a solution of 1.06g (6.43 mmol) of 4-phenylbutyric acid in 20 mL of THF at 0° C. was added193 mg (6.43 mmol) of solid NaH (80% in mineral oil). After stirring at0° C. for 0.5 h, 3.2 mL (6.43 mmol) of lithium diisopropyl amide-THFcomplex (2.0M) was added and the resulting red solution was stirred at0° C. for 45 min. To this mixture was added 765 μL (6.43 mmol) of benzylbromide and the solution was then allowed to stir overnight at roomtemperature. The reaction mixture was quenched by the slow addition ofsaturated NaHCO₃ and then washed with ether. The basic extracts wereacidified with solid KHSO₄ and partitioned with ethyl acetate. Thecombined organic extracts were washed with brine, dried over MgSO₄ andconcentrated to give 484 mg of the acid 144. ¹ H NMR consistent withstructure.

(R and S)-2-Benzyl-4-phenyl-1-butanol (145). To a solution of 469 mg(1.84 mmol) of acid 144 in 3.0 mL of THF at -78° C. was added 2.03 mL(2.03 mmol) of lithium aluminum hydride (1.0M in THF) and the resultingsolution was allowed to warm to room temperature and stirred overnight.The reaction mixture was quenched by the slow addition of Rochelle'ssalt and partitioned with ether. The combined ether extracts were washedwith water and brine and dried over MgSO₄ and concentrated. Flashchromatography (elution with 2% ether in methylene chloride) afforded264 mg of the alcohol 145. ¹ H NMR consistent with structure.

(S)-Boc-Pipecolyl-(R and S)-2-Benzyl-4-phenyl-1-butyl ester 146). Theester 146 was prepared from 264 mg (1.10 mmol) of alcohol 145, 302 mg(1.32 mmol) of (S)-Boc-L-pipecolic acid, 253 mg (1.32 mmol) of EDC and acatalytic amount of 4-pyrrolidinopyridine in 2.0 mL of CH₂ Cl₂ (mixturewas allowed to stir at room temperature for 3 days) as described abovefor the synthesis of ester 122 in Example 1. Flash chromatography(elution with 1:5:14 ether: methylene chloride:hexane) gave 375 mg ofthe diastereomeric ester 146. ¹ H NMR consistent with structure.

(R and S)-2-Benzyl-4-phenyl-1-butyl (S)-pipecolate hydrochloride salt(147). Anhydrous HCl was bubbled into a solution of 375 mg (0.83 mmol)of the ester 146 in 10 mL of EtOAc at -20° C. for 10 min and then thereaction mixture was purged with N₂. Concentration gave 352 mg of thecrude amine 147 as the hydrochloride salt. ¹ H NMR consistent withstructure.

(R and S)-2-Benzyl-4-phenyl-1-butyl(S)-N-(3,4,5-trimethoxyphenylglyoxyl)pipecolate (16). To a slurry of 54mg (0.14 mmol) of the crude amine hydrochloride 147 in 2.0 mL of CH₃ CNat room temperature was added 60 μL (0.35 mmol) ofN,N-diisopropylethylamine, 50 mg (0.21 mmol) of acid 124, and 73 mg(0.16 mmol) of the BOP reagent and the resulting mixture was stirred for3 days at room temperature and was then concentrated to dryness. Theresidue was reconstituted into 75 mL of ethyl acetate and thensequentially washed with water, 5% KHSO₄, saturated NaHCO₄ and brine andthen dried over MgSO₄ and concentrated. Flash chromatography (elutionwith 2% ether in methylene chloride) gave 52.7 mg of the diastereomericamide 16 as a rotameric mixture. ¹ H NMR (500 MHz, CDCl₃ δ 7.21-7.01(m), 5,41 (brs), 4.21 (dd), 4.08 (dd), 4.12 (d), 3.88 (d), 3.95 (s),3.91 (s), 3.49 (d), 3.39 (dt), 2.80-2.62 (m), 2.38 (brt), 2.09 (br s),1.87-1.20 (m). R_(f) 0.9 (1:3:26 Methanol: ether:methylene chloride).##STR11##

Example 7 Synthesis of (R and S)-1-Phenyl-7-(2-pyridyl)-4-heptyl(S)-N-(tert-butylglyoxyl)pipecolate (21).

(E and Z)-3-(1,3-Dioxan-2-yl)-1-(2-pyridyl)-1-propene (148 and 149). Toa suspension of 4.6 g (10.2 mmol) of[2-(1,3-dioxan-2-yl)ethyl]triphenylphosphonium bromide (Aldrich ChemicalCo.) in 50 mL of THF at 0° C. was added 6.4 mL (10.2 mmol) of n-butyllithium (1.6M in hexanes) and the resulting red solution was allowed tostir at 0° C. for 0.5 h. To this solution was added 880 μL (9.3 mmol) of2-pyridinecarboxaldehyde (Aldrich Chemical Co.). The reaction mixturewas allowed to stir at room temperature for 1 h and was then poured intowater and partitioned with ether. The combined either extracts weredried over MgSO₄ and concentrated. Flash chromatography (elution with3:1 hexane:ethyl acetate) gave 0.43 g ofE-3-(1,3-dioxan-2-yl)-1-(2-pyridyl)-1 -propene (148) and 1.12 g ofZ-3-(1,3-dioxan-2-yl)-1-(2-pyridyl)-1-propene (149). ¹ H NMRs consistentwith structures.

1-(1,3-Dioxan-2-yl)-3-(2-pyridyl)propane (150). Through a suspension of800 mg (4.2 mmol) of olefin 149 and 100 mg of 10% palladium on carbonwas bubbled a steady stream of hydrogen gas for a period of 10 min. Thereaction mixture was then filtered through celite and concentrated togive 805 mg of the acetal 150 as a colorless oil. ¹ H NMR consistentwith structure.

4-(2-Pyridyl)-1-butyraldehyde (151). A solution of 420 mg (2.2 mmol) ofacetal 150 in 4.0 mL of THF and 3.0 mL of 4N HCl was stirred at roomtemperature for 1.5 h and was then neutralized by the slow addition ofsolid NaHCO₃. The reaction mixture was extracted with ethyl acetate,dried over MgSO₄ and concentrated to yield 288 mg of the aldehyde 151. ¹H NMR consistent with structure.

(R and S)-1-Phenyl-7-(2-pyridyl)-4-heptanol (152). The alcohol 152 wasprepared from 288 mg (1.93 mmol) of aldehyde 151 and 2.3 mL (2.3 mmol)of 120 in 3.0 mL of THF as described above for the synthesis of alcohol121 in Example 1 to give 520 mg of the crude alcohol 152. ¹ H NMRconsistent with structure.

(S)-Boc-Pipecolyl-(R and S)-1-Phenyl-7-(2-pyridyl)-4-heptyl ester (153).The ester 153 was prepared from 520 mg (1.93 mmol) of alcohol 152, 442mg (1.93 mmol) of (S)-Boc-L-pipecolic acid, 370 mg (1.93 mmol) of EDCand a catalytic amount of DMAP in 4.0 mL of CH₂ Cl₂ and 4.0 mL of DMF asdescribed above for the synthesis of 122 in Example 1. Flashchromatography (elution with 3:1 hexane:ethyl acetate) gave 740 mg ofthe diastereomeric ester 153 as an oil. ¹ H NMR consistent withstructure.

(R and S)-1-Phenyl-7-(2-pyridyl)-4-heptyl (S)-pipecolate (154). Theamine 154 was synthesized by treating 740 mg (1.54 mmol) of the ester153 with 2.0 mL of trifluoroacetic acid in 5.0 mL of CH₂ Cl₂ asdescribed above for the preparation of 123 in Example 1 giving 580 mg ofthe diastereomeric amine 154 as an oil. ¹ H NMR consistent withstructure.

(R and S)-1-Phenyl-7-(2-pyridyl)-4-heptyl (S)-N-methyloxalylpipecolate(155). To a solution of 48 mg (0.13 mmol) of the amine 154 in 1.0 mL ofCH₂ Cl₂ at 0° C. was added 33 μL (0.119 mmol) ofN,N-diisopropylethylamine and 14 μL (0.15 mmol) of methyloxalyl chlorideand the resulting solution was warmed to room temperature and allowed tostir overnight. The reaction mixture was diluted with ethyl acetate,washed with saturated NH₄ Cl and brine, dried over MgSO₄ and thenconcentrated. Flash chromatography (elution with 25-30% ethyl acetate inhexane) gave 49 mg of the diastereomeric amide 155 as a mixture ofrotamers. ¹ H NMR consistent with structure.

(R and S)-1-Phenyl-7-(2-pyridyl)-4-heptyl(S)-N-(tert-butylglyoxyl)-pipecolate (21). To a solution of the amide155 in 1.2 mL of THF at -78° C. was added tert-butyl lithium dropwiseuntil TLC showed the consumption of the starting material. The reactionmixture was quenched with saturated NH₄ Cl and partitioned with ethylacetate. The combined organic extracts were washed with brine, driedover MgSO₄ and concentrated. Flash chromatography (elution with 30%ethyl acetate in hexane) gave the diasteromeric amide 21 as a mixture ofrotamers. ¹ H NMR (500 MHz, CDCl₃) δ 8.50 (t), 7.57 (t), 7.20-7.05 (m),5.23 (d), 5.18 (d), 4.56 (d), 4.44 (br d), 4.13 (d), 3.69 (br d),3.37-3.28 (m), 3.13-3.00 (m), 2.85-2.70 (m), 2.65-2.54 (m), 2.38-2.15(m), 1.82-1.65 (m), 1.56-1.44 (m), 1.55-1.30 (m), 1.27 (s), 1.21 (s).##STR12##

Example 8 Synthesis of(S)-1-[2-Oxo-2-(3,4,5-trimethoxyphenyl)acetyl]piperidine-2-carboxylicacid (R and S)-1-(3-phenylpropyl)-4-pyridin-3-yl-butyl ester (9).

(E and Z)-3-(1,3-Dioxan-2-yl)-1-(3-pyridyl)-1-propene (156). To asuspension of 9.9 g (22.4 mmol) of[2-(1,3-dioxan-2-yl)ethyl]triphenylphosphonium bromide (Aldrich ChemicalCo.) in 50 mL of THF at 0° C. was added 14.0 mL (22.4 mmol) of butyllithium (1.6M in hexanes) and the resulting red solution was allowed tostir at 0° C. for 0.5 h. To this solution was added 1.8 mL (18.7 mmol)of 3-pyridinecarboxaldehyde (Aldrich Chemical Co.) and the reactionmixture was allowed to stir at room temperature for 1.5 h and was thenpoured into water and partitioned with ether. The combined etherextracts were dried over MgSO₄ and concentrated. Flash chromatography(elution with 2:1 hexane:ethyl acetate) gave 3.3 g of the alkene 156 asa mixture of olefin isomers. ¹ H NMR consistent with structure.

1-(1,3-Dioxan-2-yl)-3-(3-pyridyl)propane (157). Through a solution of3.2 g (16.7 mmol) of olefin 156 and 300 mg of 10% palladium on carbonwas bubbled a steady stream of hydrogen gas for a period of 10 min. Thereaction mixture was then filtered through celite and concentrated togive 2.8 g of the acetal 157 as a colorless oil. ¹ H NMR consistent withstructure.

4-(3-Pyridyl)-1-butyraldehyde (158). A solution of 1.5 g (7.8 mmol) ofacetal 157 in 10.0 mL of THF and 10.0 mL of 4N HCl was stirred overnightat room temperature and was then neutralized by the slow addition ofsolid NaHCO₃. The reaction mixture was extracted with ethyl acetate,dried over MgSO₄ and concentrated to yield 1.1 g of the aldehyde 158. ¹H NMR consistent with structure.

(R and S)-1-Phenyl-7-(3-pyridyl)-4-heptanol (159). The alcohol 159 wasprepared from 1.1 g (7.4 mmol) of aldehyde 158 and 8.1 mL (8.1 mmol) of120 in 30.0 mL of THF as described above for the synthesis of 121 inExample 1 to give 1.9 g of the crude alcohol 159. ¹ H NMR consistentwith structure.

(S)-Boc-Pipecolyl-(R and S)-1-Phenyl-7-(3-pyridyl)-4-heptyl ester (160).The ester 160 was prepared from 1.65 g (6.12 mmol) of alcohol 159, 1.54g (6.73 mmol) of (S)-Boc-pipecolic acid, 1.29 g (6.73 mmol) of EDC and acatalytic amount of DMAP in 8.0 mL of CH₂ Cl₂ and 8.0 mL of DMF asdescribed above for the synthesis of 122 in Example 1. Flashchromatography (elution with 2:1 hexane:ethyl acetate) gave 1.42 g ofthe diastereomeric ester 160 as an oil. ¹ H NMR consistent withstructure.

(R and S)-1-Phenyl-7-(3-pyridyl)-4-heptyl (S)-pipecolate (161). Theamine 161 was synthesized by treating 1.42 g (2.95 mmol) of the ester160 with 2.0 mL of trifluoroacetic acid in 8.0 mL of CH₂ Cl₂ asdescribed above for the preparation of 123 in Example 1 giving 1.02 g ofthe diastereomeric amine 161 as an oil. ¹ H NMR consistent withstructure.

(R and S)-1-Phenyl-7-(3-pyridyl)-4-heptyl(S)-N-(3,4,5-trimethoxy-phenylglyoxyl)pipecolate (9). The ester 9 wasprepared from 995 mg (2.61 mmol) of the amine 161, 645 mg (2.87 mmol) ofthe acid 124 and 551 mg (2.87 mmol) of EDC in 6.0 mL of CH₂ Cl₂ asdescribed above in the synthesis of ester 3 in Example 1. Flashchromatography (elution with 3:1 acetone:hexane) gave 976 mg of thediasteromeric amide 9 as a mixture of rotamers. ¹ H NMR consistent withstructure. ##STR13##

Example 9

(R and S)-1-Phenyl-7-(3-pyridyl)-4-heptyl(S)-N-(3,4,5-trimethoxyphenylglyoxyl) pipecolate N-oxide (22). To asolution of 15 mg (0.02 mmol) of the amide 9 in 2.0 mL of CH₂ Cl₂ atroom temperature was added 9.3 μL (0.03 mmol) of 55%3-chloroperoxybenzoic acid and the resulting solution was allowed tostir overnight at room temperature. Flash chromatography (elution with100% acetone) gave 12.6 mg of the N-oxide 22 as a mixture of rotamers. ¹H NMR (500 MHz CDCl₃) δ 8.10 (m), 7.46-7.02 (m), 5.88 (d), 5.80 (d),5.06-5.00 (m), 4.95-4.89 (m), 4.61 (m), 4.31 (dd), 3.87 (s), 3.84 (s),3.83 (s), 3.81 (s), 3.78 (s), 3.50 (br d), 3.27 (ddd), 3.12 (ddd), 3.00(ddd), 2.67-2.49 (m), 2.32 (br d), 1.86-1.78 (m), 1.55-1.50 (m),1.39-1.22 (m). ##STR14##

Example 10 Synthesis of (R and S)-1-Phenyl-7-purinyl-4-heptyl(S)-N-(3,4,5-trimethoxyphenylglyoxyl)pipecolate (25).

4-Chlorobutyraldehyde (162). To a solution of 19.1 g (0.16 mol) of4-chloro-1-butanol (Aldrich Chemical Co.) in 50 mL of CH₂ Cl₂ at 0° C.was added 1.0 g of powdered 4 Å molecular sieves and 38.7 g (0.18 mol)of pyridinium dichromate and the resulting suspension was stirred at 0°C. for 45 min. The reaction mixture was diluted with ether, filteredthrough celite and concentrated. The residue was vacuum distilled (bp45°-55° C.) to yield 5.0 g of the aldehyde 162 as an oil. ¹ H NMRconsistent with structure.

(R and S)-1-Chloro-7-phenyl-4-heptanol (163). The alcohol 163 wasprepared from 182 mg (1.7 mmol) of aldehyde 162 and 1.9 mL (1.9 mmol) of120 in 20.0 mL of THF as described above for the synthesis of 121 inExample 1 to give 128 mg of the alcohol 163 (flash chromatography in100% methylene chloride). ¹ H NMR consistent with structure.

(S)-Boc-Pipecolyl-(R and S)-1-Chloro-7-phenyl-4-heptyl ester (164). Theester 164 was prepared from 128 mg (0.56 mmol) of alcohol 163, 156 mg(0.68 mmol) of (S)-Boc-pipecolic acid, 130 mg (0.68 mmol) of EDC and acatalytic amount of 4-pyrrolidinopyridine in 2.0 mL of CH₂ Cl₂ asdescribed above for the synthesis of 122 in Example 1. Flashchromatography (elution with 1:5:14 ether: methylene chloride:hexane)gave 159 mg of the diastereomeric ester 164. ¹ H NMR consistent withstructure.

(S)-Boc-Pipecolyl-(R and S)-1-Phenyl-7-purinyl-4-heptyl ester (165). Toa solution of 34 mg (0.28 mmol) of purine in 3.0 mL of DMF at roomtemperature was added 8.4 mg (0.28 mmol) of solid NaH (80% in mineraloil) and the resulting solution was allowed to stir at room temperaturefor 10 min. To this reaction mixture was added 62 mg (0.14 mmol) of theester 164 and 10 mg of NaI and this mixture was stirred overnight atroom temperature and then concentrated to dryness. The residue wasdissolved into ethyl acetate, washed sequentially with water, saturatedNaHCO₃, and brine and then dried over MgSO₄ and concentrated. Flashchromatography (elution with 15% 5:10:85 NH₄ OH:MeOH:CH₂ Cl₂ in CH₂ Cl₂)gave 56 mg of the substituted purine 165 as an oil. ¹ H NMR consistentwith structure.

(R and S)-1-Phenyl-7-purinyl-4-heptyl (S)-pipecolate hydrochloride salt(166). Anhydrous HCl was bubbled into a solution of 53.7 mg (0.10 mmol)of the ester 165 in 10 ml of EtOAc at -20° C. for 10 min and then thereaction mixture was purged with N₂. Concentration gave the crude amine166 as the hydrochloride salt. ¹ H NMR consistent with structure.

(R and S)-1-Phenyl-7-purinyl-4-heptyl(S)-N-(3,4,5-trimethoxyphenylglyoxyl)pipecolate (25). To a slurry of thecrude amine hydrochloride 166 in CH₃ CN at room temperature was added 45μL (0.26 mmol) of N,N-diisopropylethylamine, 37 mg (0.15 mmol) of acid124, and 54 mg (0.12 mmol) of the BOP reagent and the resulting mixturewas stirred at room temperature for two days and then was concentratedto dryness. The residue was reconstituted into 75 mL of ethyl acetateand then sequentially washed with water, 5% KHSO₄, saturated NaHCO₄ andbrine and then dried over MgSO₄ and concentrated. Flash chromatography(elution with 1:4:36 MeOH:Et₂ O:CH₂ Cl₂) gave 26.5 mg of thediastereomeric amide 25 as a rotameric mixture. ¹ H NMR (500 MHz, CDCl₃)δ 9.11 (s), 8.95 (m), 8.09 (m), 7.36-7.05 (m), 5.31 (m), 4.28 (m), 3.90(m), 3.46 (br t), 3.20 (m), 2.58 (m), 2.28 (br d), 2.17-1.18 (m), R_(f)0.1 (30% ether in methylene chloride). ##STR15##

Example 11 Synthesis of(S)-1-[2-Oxo-2-(3,4,5-trimethoxyphenyl)acetyl]piperidine-2-carboxylicacid (R andS)-4-[4-(morpholine-4-carbonyl)phenyl]-1-(3-phenylpropyl)butyl ester(44).

4-Formylbenzoic acid methyl ester (167). To a suspension of 9.6 g (63.6mmol) of 4-carboxybenzaldehyde (Aldrich Chemical Co.) in 100 mL of CH₂Cl₂ at 0° C. was added excess trimethylsilyldiazomethane and theresulting mixture was allowed to stir at 0° C. for 1 h. The mixture waspoured into saturated aqueous NaHCO₃ and extracted three times withethyl acetate. The combined organic extracts were dried over MgSO₄,filtered and concentrated to give 4.3 g of the ester 167 as an oil. ¹ HNMR consistent with the product.

(E and Z)-4-[3-[1,3]-Dioxolan-2-yl-propenyl)benzoic acid methyl ester(168). The olefin was prepared from 4.3 g (26.2 mmol) of the aldehyde167, 13.94 g of [1-(1,3-dioxan-2yl)ethyl]triphenylphosphonium bromideand 12.6 mL (32.0 mmol) of n-BuLi in 75 mL of THF as described for thesynthesis of 156 in Example 8. Flash chromatography (elution with 10%ethyl acetate in hexane) gave 3.27 g of the olefin 168. ¹ H NMRconsistent with the product.

4-[3-[1,3]-Dioxolan-2-yl-propyl)benzoic acid methyl ester (169). Theolefin 169 (3.21 g, 12.9 mmol) was hydrogenated over 328 mg of 10% Pd/Cin 50 mL of EtOH as described for compound 157 in Example 8. Filtrationand evaporation gave 2.85 g of 169 as an oil. ¹ H NMR consistent withthe product.

[4-(3-[1,3]-Dioxan-2-yl-propyl)phenyl]methanol (170). To a solution of2.85 g (11.4 mmol) of ester 169 in 25 mL of THF at 0° C. was added 4.4mL (24.7 mmol) of diisobutylaluminum hydride and the resulting mixturewas allowed to stir at 0° C. for 15 min. The reaction was quenched withsaturated potassium sodium tartrate and extracted three times with ethylacetate. The combined organic extracts were dried over MgSO₄, filteredand concentrated to yield 2.58 g of the crude alcohol 170 as an oil. ¹ HNMR consistent with the product.

2-[3-(4-tert-Butyldiphenylsilyloxymethylphenyl)propyl]-[1,3]-dioxolane(171). To a solution of 2.58 g (11.6 mmol) of alcohol 170 and 1.19 g(17.5 mmol) of imidazole in 50 mL of CH₂ Cl₂ was added 3.4 mL (13.1mmol) of tert-butylchlorodiphenyl silane and the resulting mixture wasallowed to stir at room temperature for 1 h. The mixture was thendiluted with ethyl acetate and washed with 0.5N HCl. The organic layerwas dried over MgSO₄, filtered and concentrated. Flash chromatography(elution with 5% ethyl acetate in hexane) afforded 5.5 g of 171. ¹ H NMRconsistent with the product.

4-(4-tert-Butyldiphenylsilyloxymethylphenyl) butyraldehyde (172). To asolution of 5.5 g (11.9 mmol) of the dioxolane 171 in 40 mL of THF atroom temperature was added 40 mL of 4.0N HCl and the resulting solutionwas allowed to stir for 1 h. The mixture was neutralized with solid K₂CO₃, extracted with ethyl acetate and concentrated. The crude mixturewas dissolved into 25 mL of CH₂ Cl₂ to which was added 600 mg (8.8 mmol)of imidazole and 1.9 mL (7.3 mmol) of tert-butylchlorodiphenyl silane.The resulting mixture was allowed to stir overnight at room temperatureand was then poured into 0.5N HCl and extracted with ethyl acetate. Theorganics were dried over MgSO₄, filtered and concentrated. Flashchromatography (elution with 8% ethyl acetate in hexane) gave 2.12 g ofthe aldehyde 172 as an oil. ¹ H NMR consistent with the product.

1-(4-tert-Butyldiphenylsilyloxymethylphenyl)-7-phenyl-heptan-4-ol (173).The alcohol 173 was prepared from 2.12 g (5.0 mmol) of 172 and 9.0 mL (9mmol) of 120 in 50 mL of THF as described for the synthesis of 121 inExample 1. Flash chromatography (elution with 10% ethyl acetate inhexane) gave 3.3 g of the alcohol 173. ¹ H NMR consistent with theproduct.

(S)-Piperidine-1,2-dicarboxylic acid (R andS)-2-[4-(4-tert-butyldiphenylsilyoxymethylphenyl)-1-3-phenylpropyl)butyl]ester1-tert-butyl ester (174). The ester 174 was prepared from 3.3 g (6.15mmol) of alcohol 173, 1.7 g (7.4 mmol) of (S)-Boc-pipecolic acid, 1.4 g(7.3 mmol) of EDC and a catalytic amount of DMAP in 35 mL of CH₂ Cl₂ asdescribed above for the synthesis of 122 in Example 1. Flashchromatography (elution with 5% ethyl acetate in hexame) provided 2.4 gof the ester 174. ¹ H NMR consistent with the product.

(S)-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (R andS)-2-[4-(4-hydroxymethylphenyl)-1-(3-phenylpropyl)butyl]ester (175). Toa solution of 750 mg (1.0 mmol) of the ester 174 in 10 mL of THF wasadded 1.1 mL (1.1 mmol) of a solution of tetrabutylammonium fluoride(1.0M in THF) and the resulting mixture was allowed to stir at roomtemperature for 15 min. The mixture was diluted with ethyl acetate,washed with 5% KHSO₄, dried over MgSO₄ and concentrated. Flashchromatography (elution with 20% ethyl acetate in hexane) gave 308 mg ofthe alcohol 175. ¹ H NMR consistent with the product.

(S)-Piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (R andS)-2-[4-(4-carboxyphenyl)-1-(3-phenylpropyl) butyl]ester (176). To asolution of 326 mg (0.64 mmol) of the alcohol 175 in 3.0 mL of acetonewas added 0.5 mL (1.27 mmol) of the Jones reagent and the resultingmixture was allowed to stir at room temperature for 1 h, and was thenfiltered through a pad of celite and concentrated. Flash chromatography(elution with 2% MeOH in CH₂ Cl₂) gave 155 mg of the acid 176. ¹ H NMRconsistent with the product.

(S)-piperidine-2-carboxylic acid (R andS)-4-(4-carboxyphenyl)-1-(3-phenylpropyl)butyl ester Trifluoroacetatesalt (177). To a solution of 155 mg (0.3 mmol) of the acid 176 in 3.0 mLof CH₂ Cl₂ was added 500 μL of trifluoroacetic acid and the resultingsolution was allowed to stir at room temperature for 3 h at which timethe volatiles were removed in vacuo. The crude residue was suspended in5.0 mL of dry benzene and the volatiles were removed to yield ananhydrous sample of the salt 177.

(S)-1- [2-Oxo-2-(3,4,5-trimethoxyphenyl)acetyl]piperidine-2-carboxylicacid (R and S)-4-(4-carboxyphenyl)-1-(3-phenylpropyl)butyl ester (178).To a suspension of 159 mg (0.3 mmol) of the salt 177 in 2.5 mL of CH₂Cl₂ at 0° C. was added 110 μL (0.63 mmol) of N,N-diisopropylethylamineand then 40 μL (0.31 mmol) of chlorotrimethylsilane and the resultingmixture was allowed to stir at 0° C. for 30 min. To this solution wasadded 85 mg (0.44 mmol) EDC and 106 mg (0.44 mmol) of the acid 124 andthe reaction mixture was allowed to stir at room temperature overnight.The mixture was diluted with ethyl acetate and washed with 0.5N HCl,water, brine, dried over MgSO₄ and concentrated. Flash chromatography(elution with 30% MeOH in CH₂ Cl₂) gave 97 mg of the product 178 as amixture of rotamers. ¹ H NMR consistent with the product.

(S)-1-[2-Oxo-2-(3,4,5-trimethoxyphenyl)acetyl]piperidine-2-carboxylicacid (R andS)-4-[4-(morpholine-4-carbonyl)phenyl]-1-(3-phenylpropyl)butyl ester(44). To a solution of 11.2 mg (17 μmol) of the acid 178 in 1.0 mL ofCH₂ Cl₂ was added 4.1 mg (21.4 μmol) of EDC and 1.8 mg (20.7 μmol) ofmorpholine and the resulting solution was allowed to stir overnight atroom temperature. Flash chromatography (elution with 20% MeOH in CH₂Cl₂) gave 7.6 mg of the amide 44 as a mixture of rotamers. ¹ H NMR (500MHz CDCl₃) δ 7.32 (d), 7.30 (d), 7.26 (s), 7.21-7.08 (m), 5.33 (m), 5.01(m), 4.92 (m), 3.92 (s), 3.89 (s), 3.88 (s), 3.87 (s), 3.86 (s), 3.85(s), 3.81-3.53 (m), 3.42 (brd), 3.29-3.21 (m), 3.05 (m), 2.61 (m), 2.42(dd), 2.31 (d), 2.12 (m), Y1.83 (m), 1.73-1.42 (m), 1.42-1.20 (m).##STR16##

Example 12--NMR DATA

We have prepared other compounds of formula (I) by methods substantiallysimilar to those described in the above Examples 1-11 and thoseillustrated in Schemes 1-3. The NMR spectral data for these compoundsare summarized below. Compounds are numbered according to the numberingscheme of Table 1.

Compound 2: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 8.42-8.33 (m), 7.51 (d), 7.42 (d), 7.38 (s), 7.31 (d),7.29-7.05 (m), 5.01 (s,br), 4.8 (m), 4.71 (m), 4.62 (m), 3.92-3.83 (m),3.81 (d), 3.60-3.51 (m), 3.50-3.45 (m), 2.65-2.51 (m), 2.50-2.39 (m),2.38-2.22 (m), 2.05 (m), 1.95 (m), 1.81-1.68 (m), 1.67-1.49 (m),1.48-1.31 (m), 1.22 (s).

Compound 5: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 7.39-6.80 (m), 6.75 (d), 5.47 (m), 4.55 (m), 4.45 (m),3.95-3.78 (m), 3.49-3.40 (m), 3.22-3.11 (m), 2.49-2.38 (m), 1.88-1.67(m), 1.61-1.42 (m), 1.37-1.14 (m).

Compound 6: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 7.36-7.19 (m), 7.18-7.02 (m), 5.77 (t), 5.65 (m), 5.39(m), 4.60-4.52 (m), 4.35 (m), 3.93-3.82 (m), 3.71-3.63 (m), 3.48-3.42(m), 3.41-3.34 (m), 3.28-3.19 (m), 3.12-3.07 (m), 2.65-2.58 (m),2.57-2.48 (m), 2.42-2.31 (m), 2.02-1.94 (m), 1.91-1.21 (m), 1.11-1.02(m).

Compound 10: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 7.35-6.98 (m), 5.35 (d), 5.3-5.14 (m), 4.52 (bd), 4.24(bs), 3.97-3.87 (m), 3.49 (t), 3.12 (q), 3.00-2.56 (m), 2.46 (t), 2.32(d), 2.18 (d), 2.11 (d), 1.93 (d), 1.83-1.56 (m), 1.55-1.38 (m),1.32-1.18 (m), 0.94-0.72 (m).

Compound 12: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers ) δ 7.37 (s ), 7.31-7.06 (m), 6.98 (d), 5.39 (dd), 5.09-5.00(m), 4.99-4.93 (m), 4.73 (d), 4.38 (m), 3.98-3.86 (m), 3.91 (s), 3.50(d), 3.34-3.24 (m), 3.09 (t), 2.73-2.16 (m), 2.02-1.24 (m).

Compound 13: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 7.38 (s ), 7.29-7.21 (m), 7.20-7.03 (m), 6.99 (d), 6.88(d), 6.82-6.73 (m), 5.40-5.32 (m), 5.04-4.98 (m), 4.97-4.91 (m), 4.61(d), 4.37 (d), 3.93-3.83 (m), 3.81-3.74 (m), 3.53-3.47 (d,br), 3.32-3.22(m), 3.11-3.04 (m), 2.65-2.12 (m), 1.97-1.21 (m).

Compound 14: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 8.04 (d), 7.97 (t), 7.59-7.48 (m), 7.47-7.41 (m),7.31-7.22 (m), 7.21-7.02 (m), 6.98-6.91 (m), 6.82-6.76 (m), 5.43-5.38(m), 5.12-5.03 (m), 4.93 (m), 4.65-4.60 (m), 4.38 (m), 3.79 (m),3.53-3.48 (m), 3.23 (q), 3.11-2.99 (m), 2.68-2.29 (m), 2.19 (t),1.98-1.31 (m).

Compound 15: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 8.05-7.92 (m), 7.78 (d), 7.47-7.03 (m), 6.42 (bs), 5.33(d), 5.01 (m), 4.94 (m), 4.59 (bd), 4.32-4.14 (m), 4.08-4.00 (m),3.97-3.84 (m), 3.77-3.68 (m), 3.45 (bd), 3.17-3.08 (m), 2.97 (t), 2.60(t), 2.48 (t), 2.35-2.21 (m), 2.11 (d), 2.05-1.10 (m), 0.91-0.79 (m).

Compound 17: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) 6 7.38-6.92 (m), 6.82-6.71 (m), 5.38-5.29 (m), , 5.06-4.85(m), 4.60 (d), 4.31 (d), 3.94-3.81 (m), 3.79-3.70 (m), 3.51-3.41 (m),3.23 (t,br), 3.06 (t), 2.62-2.22 (m), 2.15 (d), 1.82-1.29 (m).

Compound 18: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 8.55-8.38 (m), 8.08-8.00 (m), 7.98 (d), 7.68 (t), 7.59(t), 7.50-7.45 (m), 7.45-7.41 (m), 7.29-7.25 (m), 7.25-7.08 (m), 5.40(m), 5.11 (m), 4.93 (m), 4.61 (brd), 4.38 (m), 3.61 (m), 3.51-3.46 (m),3.26-3.15 (m), 3.08-2.96 (m), 2.70-2.61 (m), 2.58-2.49 (m), 2.38 (brd),2.19 (brd), 1.83-1.78 (m), 1.78-1.59 (m), 1.56-1.43 (m), 1.41-1.24 (m).

Compound 19: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) 6 8.52-8.49 (m), 8.04 (d), 7.96 (d), 7.64 (t), 7.61-7.57(m), 7.52 (t), 7.46-7.41 (m), 7.26-7.22 (m), 7.17 (t), 7.1-2-7.08 (m),5.41 (d), 5.12 (m), 4.93 (m), 4.61 (brd), 4.38 (d), 3.89-3.83 (m),3.67-3.61 (m), 3.53-3.48 (m), 3.28-3.19 (m), 3.06-3.00 (m), 2.83 (brt),2.72 (brt), 2.65 (brt), 2.52 (brt), 2.48 (brd), 2.21 (brd), 1.89-1.73(m), 1.73-1.70 (m), 1.70-1.48 (m), 1.48-1.33 (m).

Compound 20: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 8.50 (d), 7.61 (dd), 7.28-7.25 (m), 7.21-7.16 (m), 7.12(dd), 5.38 (brd), 5.09-5.02 (m), 4.93-4.90 (m), 4.62 (brd), 4.34 (m),3.94 (s), 3.92 (s), 3.91 (s), 3.90 (s), 3.89 (s), 3.49 (brddd), 3.28(ddd), 3.09 (dd), 2.83 (t), 2.74 (m), 2.63 (brd), 2.49 (dd), 2.36 (brd),2.19 (brd), 1.86-1.70 (m), 1.70-1.62 (m), 1.59-1.52 (m), 1.48-1.23 (m).

Compound 23: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 8.30 (d), 8.28 (d), 7.79 (d), 7.34 (s), 7.31-7.00 (m),6.43 (s), 5.33 (d), 5.06 (d), 4.94 (m), 4.59 (d), 4.42-4.10 (m), 4.04(s), 3.96 (s), 3.94 (s), 3.91 (s), 3.81 (s), 3.77 (s), 3.48 (d), 3.27(dt), 3.05 (dt), 2.67-2.47 (m), 2.32 (d), 2.14 (d), 2.03-1.22 (m),0.94-0.81 (m).

Compound 26: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 7.32 (d), 7.27-6.99 (m), 5.34-5.28 (m), 5.00 (s,br), 4.61(d), 4.30 (d), 3.92-3.81 (m), 3.02 (t), 2.54-2.48 (m), 2.47-2.39 (m),2.34-2.22 (m), 2.14 (d), 1.82-1.14 (m).

Compound 27: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers ) δ 8.46-8.38 (m), 7.68-7.50 (m), 7.49-7.30 (m), 7.29-7.08(m), 5.48 (m), 5.16-5.02 (m), 4.98-4.90 (m), 4.60 (d), 4.32 (d),3.51-3.42 (m), 3.26-3.12 (m), 3.11-2.98 (m), 2.65-2.42 (m), 2.32 (d,br),2.14 (d,br), 1.83-1.22 (m).

Compound 28: ¹ H NMR (500 MHz CDCl₃) (mixture of diastereomers, mixtureof rotomers) δ 8.45-8.32 (m), 7.62-7.53 (m), 7.52-7.43 (m), 7.42-7.05(m), 6.09-5.98 (m), 5.44-5.25 (m), 5.09 (s,br), 4.92 (s,br), 4.64-4.51(m), 4.31 (d), 3.50-3.41 (m), 3.24-3.12 (m), 3.07-2.94 (m), 2.68-2.45(m), 2.32 (d,br), 2.14 (d,br), 1.83-1.26 (m).

Compound 29: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 8.44-8.37 (m), 7.58-7.51 (m), 7.50-7.08 (m), 5.35 (t,br),5.10 (s,br), 4.93 (s,br), 4.68-4.54 (m), 4.32 (d), 3.51-3.42 (m),3.25-3.12 (m), 3.00 (q), 2.69-2.45 (m), 2.38-2.29 (m), 2.14 (d,br),1.82-1.20 (m).

Compound 30: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers ) δ 7.35 (s ), 7.29-7.20 (m), 7.19-7.02 (m), 6.89 (m), 6.77(m), 5.34 (d), 5.03 (m), 4.91 (m), 4.61 (d), 4.33 (d), 3.95-3.88 (m),3.48 (d), 3.31-3.21 (m), 3.05 (t,br), 2.87-2.43 (m), 2.32 (d,br), 2.18(d,br), 1.87-1.21 (m).

Compound 31: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 8.00 (s,br), 7.34 (s,br), 7.31-7.02 (m), 5.34 (s,br),5.31 (s,br), 5.03 (s,br), 4.92 (d,br), 4.61 (d,br), 4.33 (s,br),3.96-3.84 (m), 3.48 (d,br), 3.24 (s,br), 2.76-2.42 (m), 2.32 (d,br),2.15 (m), 1.87-1.20 (m).

Compound 32: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 7.38 (d), 7.30-7.08 (m), 7.07-7.03 (d), 5.35-5.31 (m),4.98 (m), 4.88 (m), 4.59 (m), 4.31 (m), 3.97-3.86 (m), 3.46 (d,br),3.29-3.18 (m), 3.04 (m), 2.65-2.42 (m), 2.35-2.22 (m), 1.83-1.14 (m),1.10 (m).

Compound 33: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 7.38 (d), 7.32-7.24 (m), 7.24 (d), 7.21 (d), 7.01 (s),7.00 (s), 6.02-5.99 (m), 5.92-5.88 (m), 5.38 (d), 5.36 (d), 4.70 (ABq),4.69 (ABq), 4.64 (ABq), 4.32 (brd), 3.91 (s), 3.89 (s), 3.88 (s), 3.74(s), 3.73 (s), 3.48 (brddd), 3.36 (brd), 3.20 (ddd), 3.06-2.97 (m), 2.62(t), 2.58 (t), 2.38 (brd), 2.21 (brd), 2.08-2.04 (m), 1.90-1.74 (m),1.73-1.46 (m), 1.38-1.33 (m), 1.24 (t).

Compound 34: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 7.33 (s), 7.30 (d), 7.29 (s), 7.28-7.20 (m), 7.18-7.11(m), 6.95-6.90 (m), 6.83 (d), 6.82 (d), 6.31-6.28 (m), 6.02-5.91 (m),5.43-5.40 (m), 5.21 (dd), 4.53 (d), 3.91 (s), 3.89 (s), 3.86 (s), 3.85(s), 3.84 (s), 3.76 (s), 3.71 (s), 3.45 (brddd), 3.40 (brddd), 3.28(ddd), 3.15 (ddd), 3.02 (ddd), 2.62 (dd), 2.40 (brd), 1.94-1.89 (m),1.87-1.67 (m), 1.65-1.50 (m).

Compound 35: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 7.34-7.29 (m), 7.28-7.11 (m), 7.10-6.93 (m), 5.35-5.28(m), 5.09-4.98 (m), 4.90 (m), 4.64-4.44 (m), 4.30 (m), 3.95-3.81 (m),3.46 (t,br), 3.31-3.19 (m), 3.03 (m), 2.66-2.38 (m), 2.34-2.25 (m), 2.16(m), 1.85-1.19 (m).

Compound 36: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 7.93-7.81 (m), 7.78 (s), 7.41-7.01 (m), 5.32 (s,br), 5.02(s,br), 4.90 (m), 4.58 (d), 4.31 (s,br), 3.95-3.80 (m), 3.45 (d), 3.22(t), 3.05 (m), 2.72-2.48 (m), 2.47 (d), 1.83-1.43 (m), 1.42-1.18 (m).

Compound 37: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 7.38 (s), 7.30 (s), 7.30-7.02 (m), 7.01 (s), 5.80-5.83(m), 5.68 (dd), 5.62 (dd), 5.38 (d), 5.36 (d), 4.66 (s), 4.65 (ABq),4.54 (s), 4.32 (brd), 4.28 (brd), 3.90 (s), 3.88 (s), 3.86 (s), 3.85(s), 3.84 (s), 3.78 (s), 3.76 (s), 3.43 (brddd), 3.39 (brddd), 3.24(ddd), 3.12 (ddd), 3.06 (ddd), 2.97 (ddd), 2.62 (t), 2.57 (t), 2.48(brd), 2.24 (brd), 2.01-1.94 (m), 1.89-1.73 (m), 1.72-1.65 (m),1.65-1.58 (m), 1.52-1.49 (m), 1.40-1.33 (m), 1.12-1.08 (m).

Compound 40: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 7.36 (s), 7.29-7.19 (m), 7.18-7.06 (m), 6.89 (m), 6.75(s), 5.32 (s,br), 4.94 (t), 3.95-3.84 (m), 3.46 (d,br), 3.22 (m), 2.82(t), 2.61 (t), 2.30 (m), 1.82-1.19 (m).

Compound 41: ¹ H NMR (500 MHz CDCl₃) (mixture of diastereomers, mixtureof rotomers) δ 7.37 (d), 7.29-7.08 (m), 7.04 (d), 5.34 (m), 4.97 (m),4.61 (d), 4.33 (m), 3.96-3.88 (t), 3.86 (d), 3.48 (d), 3.25 (m), 3.09(m), 2.65-2.52 (m), 2.48 (m), 2.32 (d), 2.18 (d), 1.86-1.49 (m)1.48-1.15 (m).

Compound 42: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 7.34 (d), 7.2 (m), 7.13 (m), 7.0-7.1 (m), 5.87 (m), 5.32(m), 5.22 (dd), 5.12 (dd), 5.0 (m), 4.89 (bm), 4.57 (bd), 4.30 (bm),3.80-3.95 (m), 3.45 (bd), 3.40 (m), 3.32 (m), 3.22 (dt), 3.05 (bm), 2.60(m), 2.52 (bm), 2.44 (m), 2.30 (m), 2.15 (bm), 1.75 (m), 1.60 (m), 1.54(m), 1.20-1.45 (bm).

Compound 43: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 7.36-7.30 (m), 7.29-7.20 (m), 7.19-7.04 (m), 5.34 (m),5.01 (s,br), 4.91 (m), 4.59 (d), 4.31 (s,br), 3.95-3.86 (m), 3.47(d,br), 3.25 (t,br), 3.14-2.90 (m), 2.68-2.52 (m), 2.45 (t), 2.32 (d),2.18 (d), 1.85-1.46 (m), 1.45-1.18 (m).

Compound 45: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 7.35 (d), 7.25 (m), 7.15 (m), 7.10 (d), 7.05 (d), 5.87(m), 5.38 (bd), 5.34 (m), 5.22 (dd), 5.14 (dd), 4.95 (bm), 4.88 (bm),4.58 (bd), 4.32 (m), 3.82-3.95 (m), 3.45 (bd), 3.40 (t), 3.25 (m), 3.05(bm), 2.60 (bm), 2.44 (m), 2.34 (bd), 2.18 (bd), 1.78 (m), 1.48-1.70(m), 1.20-1.45 (m).

Compound 46: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 7.32 (s), 7.25 (m), 7.16 (m), 7.10 (t), 5.85 (m), 5.50(dt), 5.38 (dd) 5.25 (dd), 5.18 (d), 4.58 (bm), 4.35 (bm), 4.15 (s),4.06 (d), 4.02 (d), 3.85-3.95 (m), 3.46 (bd), 3.25 (m), 3.08 (bt), 2.98(bt), 2.65 (t), 2.58 (t), 2.53 (t), 2.35 (bt), 2.20 (bd), 1.70-1.88 (m),1.50-1.70 (m), 1.20-1.42 (m).

Compound 47: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 7.44 (d), 7.42-7.06 (m), 5.45-5.30 (m), 5.12-4.91 (m),4.03-3.83 (m), 3.82-3.19 (m), 2.72-2.26 (m), 1.91-1.22 (m)

Compound 48: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 7.34 (d), 7.25 (m), 7.20 (d), 7.15 (m), 7.10 (d), 7.05(d), 5.88 (m), 5.32 (bt), 5.24 (dd), 5.14 (dd), 4.96 (m), 4.86 (m), 4.58(bd), 4.30 (bm), 3.85-3.95 (m), 3.45 (bd), 3.38 (t), 3.32 (t), 3.25 (m),3.05 (m), 2.60 (m), 2.32 (bd), 2.16 (bd), 1.78 (m), 1.48-1.72 (m),1.20-1.45 (m).

Compound 49: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers)δ 7.28-7.42, 6.57-6.61 (m), 6.45-6.51 (m), 5.80-5.87 (dd),5.70-5.77 (dd), 5.37-5.41 (brd), 5.34-5.37 (brd), 4.94-5.07 (dd),4.53-4.60 (brd), 4.35-4.38 (m), 3.80-3.95 (m), 3.74 (s), 3.38-3.50(brdd), 3.22-3.31 (ddd), 3.15-3.22 (ddd), 2.96-3.08 (m), 2.32-2.44(brdd), 1.73-1.85 (m), 1.48-1.75 (m), 1.54-1.56 (d), 1.15-1.48 (m).

Compound 50: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 7.34 (d), 7.24 (m), 7.15 (m), 7.10 (d), 7.04 (d), 5.85(m), 5.32 (m), 5.22 (dd), 5.15 (m), 5.00 (m), 4.58 (bd), 4.30 (bs),3.74-3.95 (m), 3.44 (m), 3.25 (bt), 3.04 (bm), 2.62 (m), 2.45 (t), 2.30(bd), 2.18 (bd), 1.88 (m), 1.78 (m), 1.46-1.72 (m), 1.22-1.45 (m).

Compound 51: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 7.34 (s), 7.25 (m), 7.20 (d), 7.14 (m), 7.10 (d), 7.06(d), 5.87 (m), 5.78 (dt), 5.68 (m), 5.45-5.60 (m), 5.35 (d), 5.24 (m),5.15 (d), 4.58 (bd), 3.85-3.96 (m), 3.45 (m), 3.24 (m), 3.04 (m), 2.62(m), 2.56 (t ), 2.49 (dt), 2.34 (dt), 2.18 (bm), 1.48-1.82 (m),1.24-1.40 (m).

Compound 52: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 7.40-7.03 (m), 5.38-5.28 (m), 5.02 (s,br), 4.90 (m), 4.60(d), 4.32 (s,br), 3.99-3.87 (m), 3.86-3.31 (m), 3.30-3.21 (t,br),3.11-3.02 (q,br), 2.69-2.50 (m), 2.47 (m), 2.32 (d), 2.14 (d), 1.89-1.48(m), 1.47-1.21 (m).

Compound 53: ¹ H NMR (500 MHz CDCl₃) (mixture of diastereomers, mixtureof rotomers) δ 7.40 (d), 7.35 (d), 7.30 (d), 7.28 (s), 6.60 (d), 6.55(d), 6.52 (t), 4.35 (m), 3.88-3.98 (m), 3.46 (bd), 3.21 (dt), 3.05 (dt),2.36 (bd), 2.18 (bd), 1.80 (m), 1.74 (bd), 1.64 (s), 1.56 (d), 1.48-1.55(m), 1.40 (d), 1.15-1.30 (m).

Compound 54: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 8.52 (m), 7.82-7.71 (m), 7.70-7.62 (m), 7.55-7.42 (m),7.38-7.01 (m), 5.36-5.29 (m), 5.01 (m), 4.90 (m), 4.79-4.67 (m), 4.59(d), 4.39-4.11 (m), 3.96-3.73 (m), 3.44 (d), 3.22 (t), 3.09-3.00 (q,br),2.72-2.41 (m), 2.30 (d), 2.14 (d), 1.86-1.43 (m), 1.42-1.02 (m),0.98-0.73 (m).

Compound 55: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 7.38 (d), 7.33 (d), 7.29-7.02 (m), 5.32 (m), 5.01 (m),4.90 (m), 4.59 (m), 4.30 (m), 4.08-3.51 (m), 3.46 (d), 329-3.18 (m),3.11-2.98 (q,br), 2.81-2.32 (m), 2.30 (d), 2.14 (d), 1.84-1.19 (m).

Compound 56: ¹ H NMR (500 MHz CDCl₃), (single diastereomer, mixture ofrotomers) δ 7.39-7.30 (m), 7.27-7.20 (brs), 7.20-7.15 (brt), 7.14-7.06(brd), 5.81-5.78 (brt), 5.77-5.72 (brt), 5.34-5.30 (brd), 5.28 (s),4.60-4.55 (brd), 5.33 (brs), 3.91 (s), 3.88 (s), 3.80 (brs), 3.79-3.48(m), 3.47-3.30 (brd), 3.28-3.20 (brt), 3.01-2.94 (brt), 2.66-2.60 (t),2.59-2.54 (t), 2.42-2.35 (brd), 2.25-2.19 (brd), 2.04-1.93 (m),1.89-1.73 (m), 1.72-1.65 (m), 1.64-1.57 (m), 1.54 (brs), 1.39-1.25 (m),1.20 (brs).

Compound 57: ¹ H NMR (500 MHz CDCl₃) (mixture of diastereomers, mixtureof rotomers) δ 7.32 (d), 7.31-7.01 (m), 5.31 (m), 5.00 (m), 4.90 (m),4.59 (m), 4.30 (m), 3.93-3.83 (m), 3.82-3.63 (m), 3.49-3.38 (m), 3.22(t), 3.10-2.98 (t), 2.68-2.21 (m), 2.12 (m), 1.82-1.21 (m).

Compound 58: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 7.33-7.01 (m), 5.31 (m), 4.99 (m), 4.89 (m), 4.59 (d),4.29 (m), 3.92-3.84 (m), 3.83-3.64 (m), 3.55-3.28 (m), 3.22 (t), 3.04(m), 2.63-2.22 (m), 2.14 (d), 1.81-1.21 (m).

Compound 59: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 7.71-7.52 (m), 7.42 (m), 7.39-7.04 (m), 6.72-6.59 (m),5.32 (m), 5.22 (m), 5.11 (m), 5.01 (m), 4.99-4.90 (m), 4.69-4.52 (m),4.39-4.26 (m), 3.99-3.79 (m), 3.46 (t), 3.22 (t), 3.11-2.94 (m),2.72-2.40 (m), 2.29 (t), 2.20-2.11 (m), 1.88-1.19 (m), 0.89 (m).

Compound 60: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 8.53 (m), 7.80 (m), 7.72-7.53 (m), 7.39-7.03 (m),5.36-5.28 (dd), 5.12-4.98 (m), 4.92 (m), 4.79-4.52 (m), 4.31 (m),3.98-3.81 (m), 3.45 (m), 3.31-3.19 (q,br), 3.11-3.00 (m), 2.72-2.43 (m),2.31 (d), 2.20-2.11 (m), 1.88-1.22 (m).

Compound 61: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 8.45 (s,br), 7.60-7.49 (m), 7.38-7.21 (m), 5.38-5.31 (m),5.03-4.98 (m), 3.99-3.88 (m), 3.50 (d,br), 3.29 (q), 2.65 (m), 2.38-2.31(m), 1.88-1.13 (m), 0.92-0.74 (m).

Compound 62: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 8.55-8.65 (m), 7.32-7.40 (m), 6.80-7.00 (m), 5.74-5.78(m), 5.62-5.71 (m), 5.85-5.89 (brd), 5.80-5.84 (brd), 5.13-5.21 (m),5.03-5.10 (m), 4.77-4.81 (dd), 3.87-3.94 (m), 3.80 (s), 3.79 (s), 3.72(s), 3.38-3.46 (brdd), 3.14-3.28 (m), 2.66-2.83 (m), 2.48-2.58 (m),2.28-2.48 (m), 1.32-1.18 (m).

Compound 63: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 8.62 (d), 8.61-8.58 (m), 7.64 (dd), 7.59 (dd), 7.32-7.24(m), 7.12 (d), 6.92 (dd), 6.89-6.83 (m), 6.82 (d), 6.79 (d), 6.74 (d),5.48 (d), 5.07 (d), 4.60 (m), 4.44 (brdd), 3.91 (s), 3.90 (s), 3.86 (s),3.84 (s), 3.83 (s), 3.78 (s), 3.44 (brd), 3.18 (ddd), 2.92 (ddd), 2.40(brt), 2.32 (brt), 1.89-1.70 (m), 1.62-1.48 (m).

Compound 64: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 8.59 (d), 8.58 (d), 7.32-7.04 (m), 6.99-6.80 (m), 5.62(dd), 5.61 (dd), 5.38 (dd), 5.06 (s), 5.02 (d), 4.99 (d), 4.53 (m), 4.36(m), 3.91 (s), 3.90 (s), 3.89 (s), 3.88 (s), 3.84 (s), 3.69 (s), 3.61(s), 3.46 (brd), 3.41 (brd), 3.24 (dd), 3.12 (dd), 2.62 (t), 2.58 (t),2.34 (brt), 1.99-1.92 (m), 1.86-1.42 (m).

Compound 66: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 8.56-8.51 (m), 7.35-7.28 (m), 7.27-7.22 (m), 7.14 (s),7.07 (s), 6.93-6.88 (m), 6.87-6.80 (m), 6.79-6.71 (m), 6.65-6.62 (m),5.81 (q), 5.71 (q), 5.32-5.27 (m), 5.20-4.98 (m), 4.57-4.47 (m),4.28-4.23 (m), 3.92-3.70 (m), 3.40 (brd), 3.20 (brd), 3.11 (ddd),3.00-2.89 (m), 2.33 (d), 2.26 (d), 2.20 (d), 2.07 (d), 1.80-1.57 (m),1.56-1.25 (m), 1.24-1.17 (m), 1.13-1.00 (m).

Compound 67: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 8.63-8.54 (m), 8.53-8.44 (m), 7.38-7.11 (m), 7.10-6.99(m), 6.78 (d), 6.72 (dd), 6.63 (dd), 6.53 (d), 6.44 (d), 6.14 (dd), 6.08(dd), 6.00 (dd), 5.88 (dd), 5.39 (d), 5.31 (d), 5.23-4.95 (m), 4.61-4.50(m), 4.32-4.29 (m), 3.91 (s), 3.90 (s), 3.88-3.74 (m), 3.71 (s),3.64-3.58 (m), 3.47-3.38 (m), 3.37-3.32 (m), 3.24 (ddd), 3.13 (ddd),3.07 (ddd), 2.94 (ddd), 2.62-2.45 (m), 2.38-2.29 (m), 2.20-2.11 (m),2.00-1.88 (m), 1.87-1.40 (m), 1.39-1.08 (m).

Compound 68: ¹ H NMR (500 MHz CDCl₃), (single diastereomer, mixture ofrotomers) δ 8.61 (d), 7.38 (d), 7.31 (s), 7.28-7.22 (m), 7.14 (dd), 7.10(d), 7.04 (d), 6.83 (d), 5.23 (dd), 5.14 (dd), 5.36 (d), 5.11 (brs),4.58 (m), 4.31 (m), 3.91 (s), 3.90 (s), 3.89 (s), 3.88 (s), 3.82-3.79(m), 3.78-3.64 (m), 3.51-3.44 (m), 3.40 (brd), 3.26-3.10 (m), 2.63 (dd),2.32 (brd), 2.00-1.92 (m), 1.88-1.40 (m), 1.08-1.00 (m).

Compound 69: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 8.60-8.57 (m), 8.56-8.53 (m), 7.38-7.35 (m), 7.32-7.17(m), 6.53 (s), 6.52 (s), 5.83 (q), 5.76 (q), 5.38-5.32 (m), 5.17-5.05(m), 4.67-4.60 (m), 4.30-4.28 (m), 4.13-4.08 (m), 3.96-3.82 (m), 3.80(s), 3.45 (brd), 3.28 (ddd), 2.97 (ddd), 2.77-2.72 (m), 2.53-2.43 (m),2.36-2.22 (m), 2.15-1.92 (m), 1.86-0.79 (m).

Compound 70: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 8.59-8.43 (m), 7.38-6.98 (m), 6.65 (s), 6.57 (s), 6.53(m), 6.43 (m), 5.88-5.84 (m), 5.68-5.64 (m), 5.63-5.59 (m), 5.58-5.54(m), 5.35-5.28 (m), 5.15-5.00 (m), 4.99 (d), 4.92 (d), 4.58 (d), 4.51(d), 4.33 (d), 4.26 (d), 3.89 (s), 3.87 (s), 3.83 (s), 3.79 (s), 3.72(s), 3.65 (s), 3.45-3.37 (m), 3.21 (ddd), 3.10 (ddd), 2.95-2.83 (m),2.62-2.42 (m), 2.28 (d), 2.21 (d), 1.92-1.26 (m), 1.17-1.12 (m),1.11-1.01 (m).

Compound 71: ¹ H NMR (500 MHz CDCl₃) (single diastereomer, mixture ofrotomers) δ 8.64 (d), 7.35 (d), 7.28 (s), 6.60 (d), 6.55 (d), 6.52 (t),6.49 (t), 5.86 (q), 5.78 (q), 5.42 (d), 5.08 (s), 4.64 (bd), 4.35 (m),3.88-3.98 (m), 3.46 (bd), 3.21 (dt), 3.05 (dt), 2.36 (bd), 2.18 (bd),1.80 (m), 1.74 (bd), 1.64 (s), 1.56 (d), 1.48-1.55 (m), 1.40 (d),1.15-1.30 (m).

Compound 72: ¹ H NMR (500 MHz CDCl₃), (single diastereomer, mixture ofrotomers) δ 8.62 (d), 7.35 (d), 7.28 (s), 6.60 (d), 6.50 (d), 6.45 (t),6.42 (t), 5.85 (q), 5.73 (q), 5.40 (d), 5.10 (d), 5.04 (d), 4.58 (bd),4.38 (m), 3.92 (s), 3.88 (s), 3.82 (s), 3.72 (s), 3.50 (bd), 3.30 (dt),3.01 (dt), 2.40 (bd), 2.30 (bd), 1.85 (m), 1.64 (bs), 1.56 (d), 1.48(d), 1.35-1.45 (m).

Compound 73: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 8.55-8.65 (brd), 7.32-7.42 (brdd), 7.28 (s), 7.20 (s),6.50-6.55 (m), 5.72-5.87 (m), 5.32-5.39 (m), 5.05-5.17 (m), 4.58-4.64(brd), 4.53-4.58 (brd), 4.34-4.36 (brd), 4.25-4.29 (brd), 3.71-3.96(ms), 3.40-3.48 (m), 3.23-3.30 (ddd), 3.13-3.22 (ddd), 2.17-2.37 (m),1.10-1.86 (m), 1.48-1.52 (d).

Compound 74: ¹ H NMR (500 MHz CDCl₃), (single diastereomer, mixture ofrotomers) δ 8.62-8.58 (d), 8.57-8.51 (d), 7.38-7.35 (d), 7.33-7.28 (m),7.27 (s), 7.18 (s), 6.61 (s), 6.59 (s), 5.65-5.60 (t), 5.55-5.50 (t),5.40-5.36 (d), 5.18-5.05 (m), 4.67-4.63 (brd), 4.33-4.30 (d), 3.96 (s),3.93 (s), 3.92 (s), 3.87 (s), 3.50-3.43 (brd), 3.25-3.16 (dt), 3.05-2.97(dt), 2.32-2.28 (brd), 2.14-2.08 (brd), 1.95-1.85 (m), 1.84-1.64 (m),1.63-1.56 (brd), 1.55-1.42 (m), 1.35-1.23 (m), 1.22-1.12 (m), 0.92-0.83(t), 0.73-0.68 (t).

Compound 75: ¹ H NMR (500 MHz CDCl₃), (single diastereomer, mixture ofrotomers) δ 8.62-8.58 (m), 8.57-8.53 (d), 7.41-7.39 (d), 7.38-7.35 (d),7.27 (s), 7.23 (s), 7.13 (s), 6.61 (s), 6.51 (s), 5.60-5.55 (t),5.54-5.50 (t), 5.39-5.35 (d), 5.15 (s), 5.14-5.10 (m), 5.09 (s), 5.07(s), 5.01 (s), 5.00 (s), 4.60-4.55 (brd), 4.51-4.49 (t), 4.40-4.38(brd), 3.90 (s), 3.85 (s), 3.80 (s), 3.73 (s), 3.48-3.43 (brd),3.30-3.22 (dt), 2.95-2.88 (dt), 2.38-2.32 (brd), 2.27-2.22 (brd),1.90-1.70 (m), 1.69-1.62 (brd), 1.59-1.50 (m), 1.46-1.35 (m), 1.26 (s),0.90-0.85 (t), 0.82-0.78 (t).

Compound 76: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 8.95 (s), 8.80 (d), 8.55 (m), 8.50 (m), 7.34 (s), 7.30(s), 7.28 (s), 6.76 (s), 6.73 (s), 5.85 (q), 5.77 (q), 5.40 (m),5.20-5.35 (m), 4.60 (m), 4.35 (m), 3.85-3.98 (m), 3.80 (s), 3.48 (bt),3.18-3.30 (m), 3.00 (m), 2.40 (bd), 2.32 (bd), 2.26 (bd), 1.65-1.90 (m),1.60 (s), 1.55 (dd), 1.48 (d), 1.40 (m), 1.12 (m).

Compound 77: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 8.43-8.53 (m), 7.20-7.56 (m), 7.04 (s), 7.01 (s),6.75-6.92 (m), 6.62 (brs), 5.78-5.85 (m), 5.68-5.77 (m), 5.80-5.84(brd), 5.02-5.12 (m), 3.76-4.00 (m), 3.64-3.76 (m), 3.49-3.60 (m),3.38-3.49 (m), 3.32-3.34 (d), 3.21-3.27 (m), 3.02-3.18 (m), 2.73-2.82(m), 2.37-2.53 (m), 2.24-2.32 (m), 2.20 (s), 2.15 (s), 1.27-1.72 (m),1.07-1.22 (m), 0.92-0.97 (dd), 0.82-0.86 (dd).

Compound 78: ¹ H NMR (500 MHz CDCl₃), (single diastereomer, mixture ofrotomers) δ 8.65-8.56 (d), 8.55-8.51 (d), 7.40-7.35 (d), 7.34-7.20 (m),7.16 (s), 6.70-6.60 (m), 6.21-6.18 (d), 6.15-6.11 (d), 5.97-5.88 (m),5.83-5.75 (m), 5.45-5.40 (d), 5.32 (s), 5.28 (s), 5.27 (s), 5.21-5.18(m), 5.13 (s), 5.11 (s), 4.67-4.61 (brd), 4.51-4.49 (d), 4.35-4.33 (d),4.05-4.00 (m), 3.95 (s), 3.94 (s), 3.90 (s), 3.84-3.82 (d), 3.81 (s),3.66-3.60 (q), 3.50-3.45 (brd), 3.40 (s), 3.30 (s), 3.23-3.17 (dt),3.03-2.97 (brt), 3.86-3.80 (brt), 2.60-2.55 (brt), 2.50-2.40 (m),2.30-2.25 (brd), 2.20 (s), 2.15-2.10 (brd), 1.90-1.65 (m), 1.64-1.60(brd), 1.56-1.43 (m), 1.36-1.27 (m), 1.26-1.11 (m).

Compound 79: ¹ H NMR (500 MHz CDCl₃), (single diastereomer, mixture ofrotomers) δ 8.65-8.59 (d), 8.58-8.52 (d), 7.40-7.35 (d), 7.32-7.28 (d),7.25-7.24 (d), 7.13 (s), 6.65 (s), 6.60 (s), 6.20-6.18 (d), 6.12-6.10(d), 5.97-5.90 (m), 5.89-5.75 (m), 5.43-5.38 (d), 5.33-5.20 (m), 5.16(s), 5.15 (s), 5.10 (s), 4.60-4.58 (brd), 4.51-4.49 (d), 4.40-4.38 (d),4.05-4.00 (m), 3.93-3.85 (m), 3.83 (s), 3.82 (s), 3.79 (s), 3.65-3.60(q), 3.50-3.45 (brd), 3.39 (s), 3.30-3.18 (m), 2.95-2.80 (m), 2.61-2.55(m), 2.39-2.32 (brd), 2.20 (s), 1.90-1.75 (m), 1.74-1.66 (m), 1.65-1.60(m), 1.59-1.48 (m), 1.47-1.31 (m), 1.27-1.22 (m), 1.20-1.18 (d).

Compound 80: ¹ H NMR (500 MHz CDCl₃), (single diastereomer, mixture ofrotomers) δ 8.62-8.58 (d), 8.56-8.52 (d), 7.40-7.35 (d), 7.30 (brs),7.26 (s), 7.18 (s), 6.62 (s), 6.60 (s), 5.72-5.68 (t), 5.62-5.58 (t),5.40-5.36 (d), 5.30 (s), 5.18 (s), 5.17-5.13 (d), 5.10 (s), 4.66-4.61(br d), 4.60-4.58 (m), 4.31-4.29 (br d), 3.96 (s), 3.95 (s), 3.92 (s),3.87 (s), 3.49-3.43 (br d), 3.24-3.16 (dt), 3.04-2.96 (brt), 2.32-2.28(br d), 2.17 (s), 2.13-2.06 (m), 2.91-2.85 (m), 2.81-1.64 (m), 1.63-1.55(m), 1.54-1.40 (m),.1.36-1.00 (m), 0.93-0.87 (t), 0.83-0.77 (t).

Compound 81: ¹ H NMR (500 MHz CDCl₃), (single diastereomer, mixture ofrotomers) δ 8.62-8.58 (d), 8.56-8.52 (d), 7.41-7.39 (d), 7.38-7.35 (d),7.33-7.28 (d), 7.27 (s), 7.23 (s), 7.11 (s), 6.60 (s), 6.50 (s),5.65-5.61 (t), 5.60-5.97 (t), 5.38-5.35 (d), 5.30 (s), 5.15 (s),5.13-5.10 (d), 5.08 (s), 5.06 (s), 5.01 (s), 4.59-4.54 (brd), 4.40-4.38(brd), 3.91 (s), 3.85 (s), 3.80 (s), 3.74 (s), 3.48-3.42 (brd),3.30-3.23 (dt), 2.95-2.90 (brt), 2.38-2.32 (brd), 2.18 (s), 1.90-1.75(m), 1.74-1.46 (m), 1.44-1.10 (m), 0.94-0.88 (t), 0.87-0.82 (t).

Compound 82: ¹ H NMR (500 MHz CDCl₃), (single diastereomer, mixture ofrotomers) δ 7.28-7.35 (m), 7.26 (s), 7.24 (m), 7.14 (d), 7.10 (d), 6.65(s), 6.57 (s), 5.85 (q), 5.78 (q), 5.40 (d), 5.13 (s), 5.07 (q), 5.04(s), 4.60 (bd), 4.38 (d), 3.92 (s), 3.88 (s), 3.80 (s), 3.48 (bd), 3.26(dt), 2.95 (dr), 2.40 (bd), 2.25 (bd), 1.82 (m), 1.64 (bd), 1.56 (s),1.54 (d), 1.46 (d), 1.38 (m).

Compound 83: ¹ H NMR (500 MHz CDCl₃) (single diastereomer, mixture ofrotomers) δ 7.36 (s), 7.34 (m), 7.27 (m), 7.22 (d), 7.13 (dd), 7.08(dd), 6.65 (s), 5.85 (q), 5.75 (q), 5.40 (d), 5.10 (d), 5.04 (s), 4.63(bd), 4.34 (d), 3.95 (s), 3.92 (s), 3.88 (s), 3.46 (bd), 3.22 (dt), 3.04(dt), 2.33 (bd), 2.15 (bd), 1.80 (m), 1.70 (dt), 1.55 (d), 1.46-1.58(m), 1.36 (d), 1.14 (m).

Compound 84: ¹ H NMR (500 MHz CDCl₃) (single diastereomer, mixture ofrotomers) δ 8.53 (d), 8.52 (d), 7.42 (d), 7.31 (s), 7.27 (d), 7.17 (s),6.52 (ABq), 5.81 (q), 5.74 (q), 5.10 (d), 5.04 (s), 5.03 (s), 4.58-4.50(m), 4.31 (m), 3.91 (s), 3.88 (s), 3.87 (s), 3.85 (s), 3.41 (brd), 3.18(ddd), 3.00 (ddd), 2.29 (brd), 2.12 (brd), 1.78-1.72 (m), 1.68 (brd),1.52 (d), 1.36 (d), 1.32 (d), 1.31 (d), 1.11 (m).

Compound 85: ¹ H NMR (500 MHz CDCl₃), (single diastereomer, mixture ofrotomers) δ 8.51 (d), 7.42 (d), 7.31 (s), 7.28 (d), 7.25 (s), 7.13 (s),6.58 (s), 5.80 (q), 5.76 (q), 5.33 (d), 5.10 (s), 5.02 (s), 4.56-4.50(m), 4.31 (brd), 3.90 (s), 3.88 (s), 3.81 (s), 3.79 (s), 3.46 (brd),3.24 (ddd), 2.90 (ddd), 2.33 (brd), 2.21 (brd), 1.85-1.74 (m), 1.62 (m),1.51 (d), 1.47 (d), 1.31 (d), 1.29 (d).

Compound 86: ¹ H NMR (500 MHz CDCl₃), (single diastereomer, mixture ofrotomers) δ 8.61-8.45 (m), 7.38-7.28 (m), 6.68 (s), 6.49 (s), 5.79 (q),5.61 (q), 5.19-5.01 (m) 4.72-4.63 (m), 3.89-3.67 (m), 3.65-3.45 (m),2.58 (t), 2.39-2.23 (m), 2.11-1.92 (m), 1.72-1.45 (m), 1.39-1.16 (m),0.89 (m).

Compound 87: ¹ H NMR (500 MHz CDCl₃) (single diastereomer, mixture ofrotomers) δ 8.60-8.46 (m), 7.38-7.15 (m), 6.74-6.63 (m), 6.62 (s),6.52-6.47 (m), 5.75 (q), 5.61 (m), 5.32-5.25 (m), 5.15-5.01 (m),4.72-4.59 (m), 3.93-3.80 (m), 3.75 (m), 3.62-3.43 (m), 2.39-1.55 (m),1.50 (dd), 1.36-1.21 (m).

Compound 88: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 9.16 (d), 8.74 (d), 8.70 (d) 7.85 (d), 7.50 (t), 7.27(d), 6.68 (s), 5.80 (m), 5.70 (m), 5.38 (bd), 5.31 (bd), 5.24 (s), 5.20(d), 4.60 (m), 4.34 (dd), 3.88-3.95 (m), 3.84 (s), 3.75 (s), 3.45 (bd),3.24 (dt), 3.19 (dt), 2.98 (bt), 2.34 (bd), 2.30 (bd), 2.22 (bd),1.10-1.90 (m), 1.52 (d), 1.45 (d).

Compound 89: ¹ H NMR (500 MHz CDCl₃) (single diastereomer, mixture ofrotomers) δ 7.36-7.22 (m), 5.43 (d), 5.36 (quintet), 5.25 (quintet),4.60-4.35 (m), 3.95 (s), 3.91 (s), 3.88 (s), 3.03 (d), 3.67 (d),3.47-3.40 (brd), 3.24 (dt), 3.07 (dt), 2.38 (br d), 2.22 (br d),1.85-1.60 (m), 1.58-1.25 (m).

Compound 91: ¹ H NMR (500 MHz CDCl₃) (single diastereomer, mixture ofrotomers) δ 9.01-8.93 (m), 8.78 (m), 8.06 (m), 7.75 (s), 7.68 (t), 7.61(m), 7.57 (d), 7.51-7.41 (m), 7.28-7.19 (m), 7.15 (t), 7.12-7.05 (m),7.03 (s), 5.82 (q), 5.73 (t), 5.33 (d), 4.55 (d), 4.33 (d), 3.93-3.78(m), 3.73 (s), 3.43 (d,br), 3.21 (dr), 3.01 (t), 2.63 (t), 2.58 (t),2.39 (d,br), 2.22 (d), 2.09-1.94 (m), 1.92-1.43 (m), 1.41-1.14 (m).

Compound 92: ¹ H NMR (500 MHz CDCl₃), (single diastereomer, mixture ofrotomers) δ 8.94 (d), 8.81 (m), 8.08 (m), 7.75 (s), 7.69 (t), 7.55 (d),7.48 (t), 7.42 (m), 7.31 (s), 7.29-7.07 (m), 7.02 (d), 5.81 (t), 5.71(t), 5.40 (d), 4.56 (d), 4.34 (d), 3.92-3.79 (m), 3.40 (d,br), 3.11(dr), 2.96 (t), 2.61 (t), 2.50 (m), 2.22-1.91 (m), 1.90-1.35 (m), 1.20(s), 1.02 (m), 0.83 (t). Compound 93: ¹ H NMR (500 MHz CDCl₃), (mixtureof diastereomers, mixture of rotomers) δ 8.62-8.55 (m), 7.66-7.58 (m),7.57-7.56 (m), 7.52-7.46 (m), 7.40-7.30 (m), 7.29-7.20 (m), 7.19-7.04(m), 6.96-6.79 (m), 6.77-6.69 (m), 5.85-5.77 (m), 5.70-5.62 (m),5.43-5.38 (m), 5.10-4.98 (m), 4.64-4.52 (m), 4.39-4.35 (m), 4.08-4.06(m), 4.02-3.99 (m), 3.98-3.90 (m), 3.89-3.84 (m), 3.83-3.68 (m),3.48-3.40 (m), 3.18 (ddd), 3.14 (ddd), 2.96 (ddd), 2.92 (ddd), 2.68-2.58(m), 2.57-2.51 (m), 2.37 (dd), 2.24-2.11 (m), 2.05-1.94 (m), 1.89-1.41(m), 1.40-1.23 (m), 1.22-1.10 (m).

Compound 94: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 8.61-8.55 (m), 7.47-7.40 (m), 7.38-7.02 (m), 6.92-6.88(m), 6.87-6.82 (m), 6.81-6.71 (m), 6.68-6.64 (m), 5.77-5.72 (m),5.65-5.59 (m), 5.40-5.36 (m), 5.11-5.04 (m), 5.02 (s), 4.97 (s),4.58-4.52 (m), 4.36-4.33 (m), 3.87 (s), 3.83 (s), 3.77 (s), 3.70 (s),3.57-3.52 (m), 3.48-3.36 (m), 3.24 (ddd), 3.12 (ddd), 2.99 (ddd), 2.81(ddd), 2.66-2.53 (m), 2.41-2.31 (m), 2.28-2.22 (m), 2.02-1.92 (m),1.88-1.45 (m), 1.44-1.21 (m). Compound 95: ¹ H NMR (500 MHz CDCl₃),(mixture of diastereomers, mixture of rotomers) δ 8.91-8.75 (m),7.38-7.29 (m), 7.28-7.02 (m), 6.92-6.80 (m), 6.79-6.76 (m), 6.74-6.71(m), 6.69-6.64 (m), 6.09-5.98 (m), 5.78-5.70 (m), 5.65-5.60 (m),5.40-5.34 (m), 5.32-5.26 (m), 5.19-5.13 (m), 5.09-5.00 (m), 4.63-4.52(m), 4.36-4.32 (m), 3.95-3.63 (m), 3.46 (brd), 3.41 (brd), 3.24 (ddd),3.12 (ddd), 3.02-2.92 (m), 2.67-2.45 (m), 2.41-2.30 (m), 2.27-2.21 (m),2.20-2.12 (m), 2.01-1.90 (m), 1.89-1.04 (m).

Compound 96: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 8.59-8.54 (m), 7.67-7.57 (m), 7.55-7.49 (m), 7.47-7.38(m), 7.37-7.05 (m), 6.95-6.71 (m), 5.83 (t), 5.78 (t), 5.68 (t), 5.65(t), 5.42-5.37 (m), 5.28 (s), 5.23-4.95 (m), 4.62-4.52 (m), 4.38-4.32(m), 3.93 (s), 3.92 (s), 3.88 (s), 3.87 (s), 3.47-3.38 (m), 3.18-3.07(m), 2.98-2.87 (m), 2.67-2.58 (m), 2.57-2.50 (m), 2.41-2.30 (m),2.22-2.17 (m), 2.16-2.11 (m), 2.03-1.92 (m), 1.89-1.21 (m), 1.20-1.09(m).

Compound 97: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 8.62-8.52 (m), 7.64-7.54 (m), 7.52-7.46 (m), 7.42-7.04(m), 6.97-6.78 (m), 6.77-6.70 (m), 6.12-5.97 (m), 5.85-5.76 (m),5.69-5.61 (m), 5.46-5.35 (m), 5.33-5.24 (m), 5.10-5.01 (m), 4.70-4.52(m), 4.39-4.33 (m), 3.92 (s), 3.91 (s), 3.88 (s), 3.87 (s), 3.48-3.41(m), 3.18-3.10 (m), 2.97-2.90 (m), 2.67-2.57 (m), 2.56-2.50 (m),2.42-2.31 (m), 2.23-2.10 (m), 2.04-1.93 (m), 1.89-1.10 (m).

Compound 98: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 8.59-8.53 (m), 7.67-7.44 (m), 7.39-7.03 (m), 6.94-6.78(m), 6.77-6.66 (m), 6.46-6.33 (m), 6.03-5.93 (m), 5.83 (t), 5.78 (t),5.68 (t), 5.64 (t), 5.42-5.37 (m), 5.08-4.97 (m), 4.92-4.66 (m),4.64-4.52 (m), 4.40-4.33 (m), 3.94 (s), 3.92 (s), 3.90 (s), 3.88 (s),3.87-3.84 (m), 3.48-3.40 (m), 3.20-3.08 (m), 2.98-2.88 (m), 2.64-2.57(m), 2.56-2.50 (m), 2.41-2.31 (m), 2.23-2.17 (m), 2.16-2.10(m),2.03-1.92 (m), 1.88-1.08 (m).

Compound 99: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers, mixtureof rotomers) δ 8.67-8.58 (m), 8.54-8.48 (m), 7.49-7.03 (m), 6.95-6.87(m), 6.86-6.82 (m), 6.72-6.68 (m), 5.78-5.68 (m), 5.63-5.57 (m),5.40-5.31 (m), 5.14-4.93 (m), 4.59-4.51 (m), 4.35-4.30 (m), 3.90-3.78(m), 3.73 (s), 3.71 (s), 3.45 (brd), 3.38 (brd), 3.22 (ddd), 3.11 (ddd),2.99-2.91 (m), 2.67-2.48 (m), 2.42-2.39 (m), 2.26-2.18 (m), 2.17-2.11(m), 2.05-1.92 (m), 1.89-1.18 (m), 1.09-0.98 (m).

Compound 100: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers,mixture of rotomers) δ 8.63-8.56 (m), 7.68-7.59 (m), 7.57-7.40 (m),7.39-7.20 (m), 7.19-7.04 (m), 7.03-6.98 (m), 6.97-6.81 (m), 6.78-6.71(m), 5.80 (s), 5.77 (s), 5.67 (t), 5.62 (t), 5.40-5.34 (m), 5.27-4.94(m), 4.62-4.52 (m), 4.38-4.32 (m), 3.94 (s), 3.92 (s), 3.91 (s), 3.88(s), 3.87 (s), 3.82 (s), 3.81 (s), 3.47-3.37 (m), 3.18-3.05 (m),3.00-2.90 (m), 2.68-2.50 (m), 2.43-2.29 (m), 2.22-2.09 (m), 2.07-1.95(m), 1.90-1.63 (m), 1.62-1.20 (m), 1.14-1.02 (m).

Compound 101: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers,mixture of rotomers) δ 8.64-8.58 (m), 7.43-7.30 (m), 7.29-7.19 (m),7.18-7.02 (m), 6.98-6.94 (m), 6.93-6.87 (m), 6.86-6.83 (m), 6.77-6.73(m), 5.73 (t), 5.71 (t), 5.62 (t), 5.60 (t), 5.41-5.32 (m), 5.10-5.05(m), 4.58-4.52 (m), 4.35-4.30 (m), 3.94 (s), 3.93 (s), 3.91 (s), 3.90(s), 3.88 (s), 3.84 (s), 3.83 (s), 3.78 (s), 3.76 (s), 3.45 (brd), 3.38(brd), 3.22 (ddd), 3.10 (ddd), 3.06-2.92 (m), 2.67-2.53 (m), 2.52-2.48(m), 2.42-2.29 (m), 2.28-2.11 (m), 2.04-1.94 (m), 1.88-1.20 (m),1.08-0.98 (m).

Compound 102: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers,mixture of rotomers) δ 8.63-8.57 (m), 7.66-7.60 (m), 7.58-7.54 (m),7.53-7.47 (m), 7.41-7.31 (m), 7.27-7.20 (m), 7.19-7.03 (m), 6.92-6.70(m), 5.80 (t), 5.77 (t), 5.67 (t), 5.61 (t), 5.40-5.36 (m), 5.09-5.02(m), 4.70-4.52 (m), 4.37-4.33 (m), 3.92 (s), 3.91 (s), 3.89 (s), 3.88(s), 3.87 (s), 3.86 (s), 3.85 (s), 3.82-3.77 (m), 3.48-3.40 (m),3.18-3.09 (m), 2.98-2.88 (m), 2.66-2.42 (m), 2.40-2.10 (m), 2.04-1.94(m), 1.89-1.62 (m), 1.61-1.18 (m), 1.14-1.13 (m).

Compound 103: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers,mixture of rotomers) δ 7.76-7.59 (m), 7.50-7.40 (m), 7.38-7.18 (m),7.17-7.05 (m), 6.93-6.87 (m), 6.77-6.73 (m), 6.18-6.15 (m), 5.85 (t),5.79 (t), 5.20 (t), 5.16 (t), 5.41-5.38 (m), 5.21-5.08 (m), 4.60-4.52(m), 4.37-4.32 (m), 3.92 (s), 3.91 (s), 3.88 (s), 3.87 (s), 3.47-3.37(m), 3.17-3.03 (m), 2.97-2.91 (m), 2.64-2.58 (m), 2.57-2.50 (m),2.42-2.33 (m), 2.05-1.95 (m), 1.90-1.80 (m), 1.79-1.62 (m), 1.61-1.31(m), 1.13-1.08 (m).

Compound 104: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers,mixture of rotomers) δ 7.47-7.41 (m), 7.37-7.02 (m), 5.78-5.72 (m), 5.18(t), 5.12 (t), 5.40-5.37 (m), 5.10 (s), 5.08 (s), 5.07 (s), 5.05 (s),4.59-4.51 (m), 4.37-4.31 (m), 3.87 (s), 3.85 (s), 3.77 (s), 3.73 (s),3.45 (brd), 3.37 (brd), 3.24 (ddd), 3.10 (ddd), 3.02-2.94 (m), 2.65-2.59(m), 2.58-2.53 (m), 2.52-2.46 (m), 2.43-2.35 (m), 2.27-2.22 (m),2.21-2.15 (m), 2.05-1.94 (m), 1.89-1.30 (m), 1.10-1.01 (m).

Compound 105: ¹ H NMR (500 MHz CDCl₃), (mixture of diastereomers,mixture of rotomers) δ 8.39 (d), 7.64 (q), 7.52 (q), 7.43 (m), 7.29-7.03(m), 5.02-4.88 (m), 4.60 (q), 4.46 (q), 3.62 (m), 3.52-3.38 (m),2.68-2.49 (m), 2.31-2.13 (m), 2.09-1.75 (m), 1.74-1.44 (m), 1.29-1.16(m).

Compound 106: ¹ NMR (500 MHz CDCl₃), (single diastereomer, mixture ofrotomers) δ 8.43-8.34 (m), 7.46 (ddt), 7.39 (ddt), 7.32 (s), 7.19-7.15(m), 5.32 (br d), 5.28 (s), 5.04-4.98 (m), 4.92-4.88 (m), 4.85 (br d),3.92 (s), 3.90 (s), 3.88 (s), 3.87 (s), 3.45 (br d), 3.23 (dt), 3.05(dt), 2.64-2.02 (m), 2.29 (br d), 2.13 (br d), 1.82-1.48 (m).

Compound 107: ¹ H NMR (500 MHz CDCl₃), (single diastereomer, mixture ofrotomers) δ 7.34-7.23 (m), 5.31 (quintet), 5.12 (quintet), 4.74 (dd),4.69 (dd), 4.52 (dq), 4.41 (dq), 3.93 (s), 3.90 (s), 3.82 (s), 3.70 (m),3.56-3.43 (m), 2.34-1.88 (m).

Compound 108: ¹ H NMR (500 MHz CDCl₃), (single diastereomer, mixture ofrotomers) δ 8.50-8.31 (m), 7.62 (d), 7.57 (d), 7.46 (d), 7.44-7.31 (m),7.30 (s), 7.19 (q), 7.10 (q), 5.00 (m), 4.80 (m), 4.69 (m), 4.56 (m),3.97-3.71 (m), 3.61-3.43 (m), 2.68-2.41 (m), 2.34-2.12 (m), 2.08-1.84(m), 1.83-1.72 (m), 1.71-1.42 (m), 1.29-1.13 (m).

Compound 109: ¹ H NMR (500 MHz CDCl₃) (single diastereomer, mixture ofrotomers) δ 8.48-8.32 (m), 7.53 (dd), 7.47 (m), 7.25-7.14 (m), 5.02-4.89(m), 4.79 (m), 4.49 (m), 3.73-3.55 (m), 3.48 (quintet), 3.30 (quintet),2.69-2.44 (m), 2.32-1.41 (m), 1.32-1.04 (m), 1.01 (m).

Compound 110: ¹ H NMR (500 MHz CDCl₃), (single diastereomer, mixture ofrotomers) δ 8.63-8.51 (m), 8.50-8.31 (m), 8.06 (m), 7.93-7.85 (m),7.84-7.76 (m), 7.69 (d), 7.51-7.40 (m), 7.23-7.11 (m), 7.09 (t), 5.32(d), 5.20 (m), 5.08 (m), 4.95 (m), 4.61-4.52 (m), 3.80 (m), 3.61 (m),3.39 (t), 3.21 (dt), 2.94 (dt), 2.74-2.44 (m), 2.40 (d), 2.31 (m),2.22-2.14 (m), 2.13-1.91 (m), 1.90-1.13 (m).

Compound 110: ¹ H NMR (500 MHz CDCl₃) (single diastereomer, mixture ofrotomers) δ 8.46-8.36 (m), 7.61 (dd), 7.52 (dd), 7.50-7.40 (m),7.22-7.15 (m), 6.87 (dd), 6.83 (dd), 6.07 (s), 6.04 (dd), 5.35 (d),5.10-5.06 (m), 4.98-4.92 (m), 4.6 (br d), 4.34 (d), 3.4 (br d), 3.15(dr), 2.98 (dt), 2.68-2.50 (m), 2.24 (br d), 1.8-1.46 (m), 1.37-1.24(m).

Compound 112: ¹ H NMR (500 MHz CDCl₃), (single diastereomer, mixture ofrotomers) δ 8.7 (d), 8.6 (d), 7.7.-7.6 (dd), 7.45 (s), 7.3-7.2 (m), 6.9(d), 6.1 (d), 5.3 (m), 4.6 (d), 4.4 (d), 3.45 (dd), 3.4-3.3 (m), 3.1-2.9(m), 2.85-2.8 (m), 2.4 (dd), 1.97-1.7 (m), 1.6-1.35 (m).

Compound 113: ¹ H NMR (500 MHz CDCl₃), (single diastereomer, mixture ofrotomers) δ 8.7 (d), 8.6 (d), 8.5 (m), 7.7-7.6 (dd), 7.3 (s), 7.2 (m),5.4 (d), 5.3 (m), 4.6 (brd), 4.4 (brd), 3.95 (s), 3.90 (s), 3.85 (s),3.45 (dd), 3.3-3.2 (dd), 3.1-2.9 (m), 2.4 (dd), 1.95 (s), 1.9-1.7 (m),1.6-1.35 (m).

Compound 114: ¹ H NMR (500 MHz CDCl₃), (single diastereomer, mixture ofrotomers) δ 8.49 (d), 7.52 (q), 7.31 (s), 7.18 (s), 7.12-6.99 (m), 5.31(d), 4.99 (m), 4.54 (d), 3.92-3.79 (m), 3.42 (d,br), 3.22 (dt), 3.02(dt), 2.81-2.62 (m), 2.60 (t), 2.30 (d,br), 2.13 (d), 1.82-1.19 (m).

Compound 115: ¹ H NMR (500 MHz CDCl₃), (single diastereomer, mixture ofrotomers) δ 8.63-8.53 (m), 7.43-7.37 (d), 7.35-7.23 (m), 7.17 (s), 6.56(s), 6.54 (s), 5.48-5.42 (d), 5.41-5.38 (d), 5.32-5.29 (d), 5.20-5.10(m), 4.68-4.62 (brd), 4.32.-4.30 (d), 4.00-3.90 (m), 3.86 (s), 3.53-3.47(brd), 3.25-3.20 (dt), 3.05-3.00 (dt), 2.37-2.21 (brd), 2.10-2.00 (m),1.92-1.87 (m), 1.80-1.70 (m), 1.69-1.59 (m), 1.57-1.43 (m), 1.34-1.15(m), 0.97-0.92 (d), 0.85-0.78 (d), 0.77-0.75 (d), 0.66-0.64 (d).

Compound 116: ¹ H NMR (500 MHz CDCl₃), (single diastereomer, mixture ofrotomers) δ 8.65-8.55 (m), 7.42-7.40 (d), 7.39-7.37 (d), 7.33-7.30 (d),7.26 (s), 7.22 (s), 7.10 (s), 6.60 (s), 6.42 (s), 5.42-5.40 (d),5.39-5.37 (d), 5.34-5.32 (d), 5.16 (s), 5.15-5.11 (m), 5.10 (s),5.07-4.94 (q), 4.60-4.55 (brd), 4.41-4.39 (brd), 3.93 (s), 3.84 (s),3.80 (s), 3.70 (s), 3.48-3.43 (brd), 3.30-3.22 (dt), 2.96-2.90 (dt),2.39-2.35 (brd), 2.29-2.25 (brd), 2.05-2.00 (m), 1.90-1.75 (m),1.65-1.60 (m), 1.59-1.48 (m), 1.47-1.33 (m), 0.95-0.87 (d), 0.86-0.83(d), 0.82-0.78 (d), 0.73-0.69 (d).

Compound 117: ¹ H NMR (500 MHz CDCl₃), (single diastereomer, mixture ofrotomers) δ 8.65-8.60 (d), 8.59-8.52 (d), 7.45-7.39 (d), 7.38-7.23 (m),7.21 (s), 6.67 (s), 6.66 (s), 5.83-5.79 (t), 5.78-5.75 (t), 5.74-5.63(m), 5.53-5.48 (m), 5.45-5.41 (brd), 5.20-5.05 (m), 5.04 (s), 5.01 (s),4.99 (s), 4.72-4.68 (brd), 4.35-4.32 (brd), 3.98 (s), 3.97 (s), 3.93(s), 3.90 (s), 3.85 (s), 3.55-3.48 (brd), 3.32-3.24 (dt), 3.10-3.03(dt), 2.70-2.62 (m), 2.61-2.56 (m), 2.55-2.45 (m), 2.39-2.32 (brd),2.20-2.15 (brd), 1.97-1.70 (m), 1.69-1.60 (m), 1.59-1.47 (m), 1.40-1.20(m), 0.93-0.90 (m).

Compound 118: ¹ H NMR (500 MHz CDCl₃), (single diastereomer, mixture ofrotomers) δ 8.66-8.62 (d), 8.61-8.59 (d), 7.46-7.44 (d), 7.43-7.40 (d),7.39-7.33 (d), 7.31 (s), 7.28 (s), 7.16 (s), 6.68 (s), 6.57 (s),5.80-5.75 (t), 5.74-5.67 (m), 5.43-5.40 (d), 5.20-5.05 (m), 4.64-4.60(brd), 4.43-4.41 (brd), 3.96 (s), 3.90 (s), 3.85 (s), 3.78 (s),3.53-3.49 (brd), 3.35-3.28 (dt), 3.02-2.96 (brt), 2.70-2.50 (m),2.42-2.36 (brd), 2.32-2.29 (brd), 1.91-1.78 (m), 1.73-1.68 (brd),1.63-1.55 (m), 1.50-1.40 (m).

Example 13--MDR Sensitization Assays

To assay the ability of the compounds according to this invention toincrease the antiproliferative activity of a drug, cell lines which areknown to be resistant to a particular drug may be used. These cell linesinclude, but are not limited to, the L1210, P388D, CHO and MCF7 celllines. Alternatively, resistant cell lines may be developed. The cellline is exposed to the drug to which it is resistant, or to the testcompound; cell viability is then measured and compared to the viabilityof cells which are exposed to the drug in the presence of the testcompound.

We have carried out assays using L1210 mouse leukemia cells transformedwith the pHaMDR1/A retrovirus carrying a MDR1 cDNA, as described byPastan et al., Proc. Natl. Acad. Sci., Vol. 85, 4486-4490. (1988). Theresistant line, labelled L1210VMDRC.06, was obtained from Dr. M. M.Gottesman of the National Cancer Institute. These drug-resistanttransfectants had been selected by culturing cells in 0.06 mg/mlcolchicine.

Multi-drug resistance assays were conducted by plating cells (2×10³,1×10⁴, or 5×10⁴ cells/well) in 96 well microtiter plates and exposingthem to a concentration range of doxorubicin (50 nM-10 μM) in thepresence or absence of multi-drug resistance modifier compounds ("MDRinhibitors") of this invention (1, 2.5 or 10 μM) as described in Ford etal., Cancer Res., Vol. 50, 1748-1756. (1990). After culture for 3 days,the viability of cells was quantitated using MTT (Mossman) or XTT dyesto assess mitochondrial function. All determinations were made inreplicates of 4 or 8. Also see, Mossman T., J. Immunol. Methods, Vol.65, 55-63 (1983).

Results were determined by comparison of the IC₅₀ for doxorubicin aloneto the IC₅₀ for doxorubicin+MDR inhibitor. An MDR ratio was calculated(IC₅₀ Dox/IC₅₀ Dox+Inhibitor) and the integer value used for comparisonof compound potencies.

In all assays, compounds according to this invention were tested forintrinsic antiproliferative or cytotoxic activity. The results aresummarized in Table 2 below. As demonstrated in Table 2, the compoundsgenerally caused <10% cytotoxicity at concentrations of 10 μM orgreater.

Compounds of formula (I) have also been assayed for MDR sensitizationactivity with other MDR cell lines including several human cell lines(e.g., myeloma cells (8226/DOX6, 8226/DOX40, MDR10V, MR 20), melanomacells (VCR 4.5, VBL 3.0, COL-1), GM3639 T cells, MCF-7 breast carcinoma,A549 bronchogenic adenocarcinoma, LOX melanoma, P388/ADR, and P388VMDRC.04), and different chemotherapeutic drugs (e.g., doxorubicin,vincristine, vinblastine, taxol, colchicine, and etoposide). Resultssimilar to those shown in Table 2 were obtained in these assays (datanot shown), further demonstrating the effectiveness of the compounds ofthis invention in multi-drug resistance sensitization.

                                      TABLE 2                                     __________________________________________________________________________    Evaluation of Compounds for Reversal of Multidrug Resistance                                           MDR MDR MDR                                              IC.sub.50 Dox                                                                      IC.sub.50 +                                                                       IC.sub.50 Dox +                                                                     IC.sub.50 Dox +                                                                     Ratio                                                                             Ratio                                                                             Ratio                                        Cmpd                                                                              Alone                                                                              1 μM                                                                           2.5 μM                                                                           10 μM                                                                            1 μM                                                                           2.5 μM                                                                         10 μM                                     __________________________________________________________________________     2   900 nM                                                                            400       <60   2.25    >15                                           4   800 400       <60   2       2.7                                           6   900 300       <60   3       >15                                           8   800 500        100  1.6     8                                            10  6500     625             10.4                                             11   700 200       <60   3.5     >12                                          12  6500     350             18.6                                             15   800 400       <60   2       >13                                          21  1000 700        90   1.4     11.1                                         27  1200 900        200  1.3     6                                            31  1300 900        500  1.4     2.6                                          43  6500     600             10.8                                             44   400 200       <60   2       >6                                           47   900 800        100  1.1     9                                            48  1400 800        100  1.75    14                                           49  5000     700             7.1                                              52   900 500       <60   1.8     >15                                          53  1600 700        200  2.3     8                                            54  6500     510             12.7                                             55   900 400       <60   2.25    >15                                          56   400 300       <60   1.3     >7                                           64  1500 700        400  2.1     3.75                                         66  1600 1300       400  1.3     4                                            69   800 400       <60   2       >13                                          84  6000     350             17.1                                             98  6000     2000            3                                                105 9000 2800       500  3.2     18                                           CsA 1800  80             22.5                                                 FK506                                                                              400 400        100  1       4                                            __________________________________________________________________________

Example 14--Immunosuppression (Mitogenesis) Assays Cell Source andCulture

Fresh peripheral blood lymphocytes (PBLs) from LeukoPak cells or wholeblood from random normal blood donors (tested HIV-negative and hepatitisnegative) were isolated and separated by density centrifugation overHistopaque 1077 (Sigma Chemical Co., St. Louis, Mo.). The murine CTLLcytotoxic T cell line and the human Jurkat T cell line were from ATCC(CTLL-2 ATCC TIB214, JURKAT CLONE E6-1 ATCC TIB152). The humanallogeneic B cell lines used for activation of the fresh PBLs wereEBV-transformed lymphocytes from normal healthy adult donors with twocompletely different HLA haplotypes. All cell lines were routinelytested for the presence of Mycoplasma contamination using the GibcoMycotect test kit and found to be Mycoplasma-free. Culture mediumconsisted of RPMI 1640 (Gibco, Grand Island, N.Y.) containing penicillin(50 U/ml) and streptomycin (50 μg/ml), L-glutamine 2 mM, 2mercaptoethanol (5×10⁻⁵), 10% heat-inactivated FCS and 10 mM HEPES.

Compound Solutions and Titrations

All chemical stocks were dissolved in DMSO. Titrations of compounds weremade into the medium the individual assay was carried out in, i.e.,complete RPMI or HB 104 for final diluted concentrations, using multiplethree-fold dilutions from 1 μM or 10 μM stock solutions.

Mitogenesis Assays ("PMA" and "OKT3")

The inhibitory effect of test compounds on the proliferation of humanPBLs in response to mitogens (Waithe, W. K. and K. Hirschhorn, Handbookof Experimental Immunology, 3d Ed. Blackwell Scientific Publications,Oxford (1978); Mishell, B. B. and S. M. Shiigi, Selected Methods inCellular Immunology W. H. Freeman and Co., San Francisco, Calif. (1980))was assessed by stimulation of 5×10⁴ cells with OKT3 (10⁻⁴ dilutionfinal) or PMA (10 ng/ml) plus ionomycin (250 ng/ml) in the presence orabsence of different concentrations of test compounds and control drugs(CsA, FK506, rapamycin) in final volume of 200 μl per well in 96 wellround bottomed plates. After 48 h incubation (37° C., 5% CO₂), cellswere pulsed with 1 μCi of ³ H-Leucine, harvested 24 h later with a TomTek cell harvester, and counted in LKB β-scintillation counter. Results(cpm) were compared with controls with medium alone, and concentrationscausing 50% reduction in counts (IC₅₀) were calculated. The results aresummarized in Table 3 below.

                  TABLE 3                                                         ______________________________________                                        PMA and OKT3 - Induced Proliferation Assay                                    Cmpd.        PMA (μM)                                                                             OKT3 (μM)                                           ______________________________________                                         3           >10       17.5                                                    4           >10       >17.5                                                   5           >17.5     >17.5                                                   6           7.5       >17.5                                                   7           >17.5     >17.5                                                   8           14.6      17.5                                                    9           5.6       6.0                                                    10           >7.6      >17.5                                                  11           >7.6      >17.5                                                  12           8.2       17.5                                                   13           9.3       15.0                                                   14           >8.3      >15                                                    15           6.7       9.0                                                    16           9.0       >15.0                                                  17           >15.0     >15.0                                                  18           6.3       >9.0                                                   19           7.8       9.8                                                    20           5.5       >9.0                                                   21           >9.0      12.6                                                   22           10.0      4.6                                                    23           8.0       4.0                                                    25           8.7       3.8                                                    26           >17.0     >12.5                                                  27           10.0      37.5                                                   28           >8.7      >8.7                                                   29           >50.0     >50.0                                                  30           >20.0     >23.3                                                  31           7.5       15.0                                                   32           >10.0     >30.0                                                  33           >9.0      >10.0                                                  34           50.0      50.0                                                   35           6.5       9.5                                                    36           33.0      40.0                                                   37           5.0       6.0                                                    40           10.0      50.0                                                   41           20.0      >50.0                                                  44           10.0      10.0                                                   45           10.0      10.0                                                   47           >10.0     >10.0                                                  56           >10.0     >10.0                                                  57           6.0       7.0                                                    62           10.0      9.0                                                    64           7.5       9.5                                                    65           6.0       10.0                                                   67           5.0       5.0                                                    68           5.0       2.2                                                    69           10.0      3.0                                                    70           2.5       2.5                                                    71           10.0      3.5                                                    72           8.2       3.2                                                    73           2.7       2.0                                                    74           7.5       >10.0                                                  75           >10.0     7.0                                                    76           10.0      1.0                                                    77           6.5       6.0                                                    78           10.0      9.0                                                    79           10.0      2.5                                                    80           4.0       1.9                                                    81           9.0       NT                                                     84           7.0       3.2                                                    85           10.0      5.0                                                    88           >10.0     >6.5                                                   91           7.0       10.0                                                   92           7.0       4.5                                                    93           7.0       7.0                                                    94           >10.0     >10.0                                                  95           >10.0     >10.0                                                  96           >10.0     >10.0                                                  97           9.0       9.0                                                    98           >10.0     >10.0                                                  99           >10.0     >10.0                                                  100          >10.0     >10.0                                                  101          4.0       1.0                                                    102          2.5       9.5                                                    105          >9.0      >12.6                                                  115          5.0       5.0                                                    116          >10.0     5.0                                                    117          8.5       7.0                                                    118          7.3       3.3                                                    ______________________________________                                         NT = Not Tested                                                          

The above results demonstrate the efficacy of the compounds of thisinvention against mitogen-induced proliferation, and asimmunosuppressive agents.

While we have described a number of embodiments of this invention, it isapparent that our basic constructions may be altered to provide otherembodiments which utilize the products, processes and methods of thisinvention. Therefore, it will be appreciated that the scope of thisinvention is to be defined by the appended claims, rather than by thespecific embodiments which have been presented by way of example.

We claim:
 1. A compound of formula (I): ##STR17## wherein: A is O, NH,or N--(C1-C4 alkyl);B and D are independently:(i) Ar₂,(C5-C7)-cycloalkyl substituted (C1-C6)-straight or branched alkyl or(C2-C6)-straight or branched alkenyl, (C5-C7)-cycloalkenyl substituted(C1-C6)-straight or branched alkyl or (C2-C6)-straight or branchedalkenyl, or Ar₂ -substituted (C1-C6)-straight or branched alkyl or Ar₂-substituted (C2-C6)-straight or branched alkenyl, wherein in each case,any one of the CH₂ groups in said alkyl or alkenyl chains is optionallyreplaced by a heteroatom selected from the group consisting of O, S, SO,SO₂ ; or (ii) ##STR18## wherein Q is hydrogen, (C1-C6)-straight orbranched alkyl or (C2-C6)-straight or branched alkenyl; wherein T is Ar₂or substituted 5-7 membered cycloalkyl with substituents at positions 3and 4 which are independently selected from the group consisting ofhydrogen, oxo, hydroxyl, O--(C1-C4-alkyl) and O--(C2-C4-alkenyl);whereinAr₂ is selected from the group consisting of phenyl, 1-naphthyl,2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, and other monocyclic and bicyclic heterocyclicring systems with individual ring sizes of 5 or 6 which may contain ineither or both rings a total of 1 to 4 heteroatoms independentlyselected from oxygen, nitrogen and sulfur; wherein any occurrence of Ar₂optionally contains one to three substituents which are independentlyselected from the group consisting of hydrogen, halogen, hydroxyl,hydroxymethyl, nitro, trifluoromethyl, trifluoromethoxy,(C1-C6)-straight or branched alkyl, (C2-C6)-straight or branchedalkenyl, O-((C1-C4)-straight or branched alkyl), O--((C2-C4)-straight orbranched alkenyl), O-benzyl, O-phenyl, 1,2-methylenedioxy, amino,carboxyl and phenyl; L is U; M is either oxygen or CH--U; provided thatif L is hydrogen, then M is CH--U or if M is oxygen then L is nothydrogen;wherein U is hydrogen, O--((C1-C4)-straight or branched alkyl),O--((C2-C4)-straight or branched alkenyl), (C1-C6)-straight or branchedalkyl, (C2-C6)-straight or branched alkenyl, (C5-C7)-cycloalkyl,(C5-C7)-cycloalkenyl substituted with (C1-C4)-straight or branched alkylor (C2-C4)-straight or branched alkenyl, ((C1-C4)-alkyl or(C2-C4)-alkenyl)-Ar₂ or Ar₂ (Ar₂ as defined above); J and K are takentogether with the N and C atom to which they are respectively attachedto form a 5-7 membered heterocyclic ring containing only one N atom; mis 0-3; and the stereochemistry at carbon positions 1 and 2 areindependently (R) or (S).
 2. A compound of formula (I): ##STR19##wherein: A is CH₂, oxygen, NH or N--(C1-C4 alkyl);B and D areindependently(i) Ar₁, (C1-C10)-straight or branched alkyl,(C2-C10)-straight or branched alkenyl or alkynyl,(C5-C7)-cycloalkyl-substituted (C1-C6)-straight or branched alkyl or(C2-C6)-straight or branched alkenyl or alkynyl,(C5-C7)-cycloalkenyl-substituted (C1-C6)-straight or branched alkyl or(C2-C6)-straight or branched alkenyl or alkynyl, or Ar₁ -substituted(C1-C6)-straight or branched alkyl or (C2-C6)-straight or branchedalkenyl or alkynyl wherein, in each case, any one of the CH₂ groups ofsaid alkyl, alkenyl or alkynyl chains is optionally replaced by aheteroatom selected from the group consisting of O, S, SO, SO₂ ; or (ii)##STR20## wherein Q is hydrogen, (C1-C6)-straight or branched alkyl or(C2-C6)-straight or branched alkenyl or alkynyl; wherein T is Ar₁ orsubstituted 5-7 membered cycloalkyl with substituents at positions 3 and4 which are independently selected from the group consisting of oxo,hydrogen, hydroxyl, O--(C1-C4)-alkyl or O--(C2-C4)-alkenyl; providedthat at least one of B or D is independently selected from the groupconsisting of (C2-C10)-straight or branched alkynyl,(C5-C7)-cycloalkyl-substituted (C2-C6)-straight or branched alkynyl,(C5-C7)-cycloalkenyl-substituted (C2-C6)-straight or branched alkynyl,and Ar₁ -substituted (C2-C6)-straight or branched alkynyl;wherein Ar₁ isa carboxylic aromatic group selected from the group consisting ofphenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, andanthracenyl; or a heterocyclic aromatic group selected from the groupconsisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl,1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl,pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl,indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl,benzo[b]thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl,purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl,pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, andphenoxazinyl; wherein any occurrence of Ar₁ optionally contains one tothree substituents which are independently selected from the groupconsisting of hydrogen, halogen, hydroxyl, hydroxymethyl, nitro,trifluoromethyl, trifluoromethoxy, (C1-C6)-straight or branched alkyl,(C2-C6)-straight or branched alkenyl, O--((C1-C4)-straight or branchedalkyl), O--((C2-C4)-straight or branched alkenyl), O-benzyl, O-phenyl,1,2-methylenedioxy, amino, carboxyl, N-((C1-C5)-straight or branchedalkyl or (C2-C5)-straight or branched alkenyl) carboxamides,N,N-di-((C1-C5)-straight or branched alkyl or (C2-C5)-straight orbranched alkenyl)carboxamides, N-morpholinocarboxamide,N-benzylcarboxamide, N-thiomorpholinocarboxamide,N-picolinoylcarboxamide, O--X, CH₂ --(CH₂)_(q) --X, O--(CH₂)_(q) --X,(CH₂)_(q) --O--X, and CH═CH--X;wherein X is 4-methoxyphenyl, 2-pyridyl,3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazoyl,isoxazoyl, 2-methylthiazoyl, thiazoyl, 2-thienyl, 3-thienyl, orpyrimidyl; and q is 0-2; L is U; M is either oxygen or CH--U; providedthat if L is hydrogen, then M is CH--U or if M is oxygen, then L is nothydrogen;wherein U is hydrogen, O--((C1-C4)-straight or branched alkyl)or O--((C2-C4)straight or branched alkenyl), (C1-C6)-straight orbranched alkyl or (C2-C6)-straight or branched alkenyl,(C5-C7)-cycloalkyl or (C5-C7)-cycloalkenyl substituted with(C1-C4)-straight or branched alkyl or (C2-C4)-straight or branchedalkenyl, ((C1-C4)-alkyl or (C2-C4)-alkenyl)--Y or Y;wherein Y is acarboxylic aromatic group selected from the group consisting of phenyl,1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, and anthracenyl;or a heterocyclic aromatic group as defined above; wherein Y optionallycontains one to three substituents which are independently selected fromthe group consisting of hydrogen, halogen, hydroxyl, nitro,trifluoromethyl, trifluoromethoxy, (C1-C6)-straight or branched alkyl,(C1-C6)-straight or branched alkenyl, O--((C1-C4)-straight or branchedalkyl), O--((C2-C4)-straight or branched alkenyl), O--benzyl, O-phenyl,1,2-methylenedioxy, amino, and carboxyl; J and K are taken together withthe N and C atom to which they are respectively attached to form a 5-7membered heterocyclic ring containing only one N atom; andm is 0-3. 3.The compound according to claim 2, wherein said Ar₁ group contains oneto three substituents selected from the group consisting ofN-((C1-C5)-straight or branched alkyl or (C2-C5)-straight or branchedalkenyl) carboxamides, N,N-di-((C1-C5)-straight or branched alkyl oralkenyl)carboxamides, N-morpholinocarboxamide, N-benzylcarboxamide,N-thiomorpholinocarboxamide, N-picolinoylcarboxamide, O--X, CH₂--(CH₂)_(q) --X, O--(CH₂)_(q) --X, (CH₂)_(q) --O--X, and CH═CH--X;wherein X is 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl,quinolyl, 3,5-dimethylisoxazoyl, isoxazoyl, 2-methylthiazoyl, thiazoyl,2-thienyl, 3-thienyl, or pyrimidyl, and q is 0-2.
 4. The compoundaccording to any one of claims 1-3, wherein in formula (I), M is O and Jand K are taken together to form a pyrrolidine or a piperidine ring. 5.The compound according to claim 4, wherein in formula (I),B is selectedfrom the group consisting of 3-(2-pyridyl)propyl, 3-phenylpropyl,2-phenoxypropyl, phenyl, 2(3-pyridyl)ethyl,E-2-[trans-(4-hydroxycyclohexyl)]-1-methyl-ethenyl, 3-(3-pyridyl)propyl,benzyl, 2-phenylethyl, 2-(4-methoxyphenyl)ethyl,3-(N-benzimidazolyl)propyl, 3-(4-methoxyphenyl)propyl,3-[N-(7-azaindolyl)]propyl, 3-(N-purinyl)propyl,3-(3-pyridyl)propyl-N-oxide, 3-(4-hydroxymethylphenyl) propyl,3-(2-thienyl)propyl, 3-(4-carboxyphenyl)propyl, 4-phenylbutyl,2-hydroxymethyl-phenyl, 2-allyloxyphenyl, 3-(3-hydroxymethylphenyl,2-hydroxyphenyl, 3-pyridyl and 5-phenylpentyl; D is selected from thegroup consisting of 3-phenylpropyl, 2-phenoxyphenyl,3-(3-indolyl)propyl, 2-phenylethyl, 4-phenylbutyl, and3-(4-methoxyphenyl)propyl; and L is selected from the group consistingof 3,4,5-trimethoxyphenyl, phenyl, tert-butyl, 3-benzyloxy-phenyl,3-allyloxyphenyl and 3-isopropoxyphenyl.
 6. A compound of formula (II):##STR21## wherein n, m, B, D and U are defined as follows:

    ______________________________________                                        n   m     B          D         U                                              ______________________________________                                        1   0     3-(Pyridin-2-                                                                            3-Phenylpropyl                                                                          3,4,5-Trimethoxyphenyl                                   yl)propyl                                                           2   0     3-Phenyl-  3-Phenylpropyl                                                                          3,4,5-Trimethoxyphenyl                                   propyl                                                              2   0     2-Phenoxy- 3-Phenylpropyl                                                                          3,4,5-Trimethoxyphenyl                                   phenyl                                                              2   0     Phenyl     2-Phenoxy-                                                                              3,4,5-Trimethoxyphenyl                                              phenyl                                                   2   0     Phenyl     3-Phenylpropyl                                                                          3,4,5-Trimethoxyphenyl                         2   0     2-(Pyridin-3-                                                                            3-Phenylpropyl                                                                          3,4,5-Trimethoxyphenyl                                   yl)ethyl                                                            2   0     E-3-[trans-(4-                                                                           3-Phenylpropyl                                                                          3,4,5-Trimethoxyphenyl                                   Hydroxy-                                                                      cyclohexyl)]-                                                                 2-methyl-eth-                                                                 2-enyl                                                              2   0     3-(Pyridin-3-                                                                            3-Phenylpropyl                                                                          3,4,5-Trimethoxyphenyl                                   yl)propyl                                                           2   0     Benzyl     3-Phenylpropyl                                                                          3,4,5-Trimethoxyphenyl                         2   0     Benzyl     3-(Indol-3-yl)                                                                          3,4,5-Trimethoxyphenyl                                              propyl                                                   2   0     2-Phenylethyl                                                                            3-Phenylpropyl                                                                          3,4,5-Trimethoxyphenyl                         2   0     2-(4-Methoxy-                                                                            3-Phenylpropyl                                                                          3,4,5-Trimethoxyphenyl                                   phenyl)ethyl                                                        2   0     2-(4-Methoxy-                                                                            3-Phenylpropyl                                                                          Phenyl                                                   phenyl)ethyl                                                        2   0     3-(N-      3-Phenylpropyl                                                                          3,4,5-Trimethoxyphenyl                                   Benzimida-                                                                    zolyl)propyl                                                        2   1     Benzyl     2-Phenylethyl                                                                           3,4,5-Trimethoxyphenyl                         2   0     3-(4-Methoxy-                                                                            3-Phenylpropyl                                                                          3,4,5-Trimethoxyphenyl                                   phenyl)                                                                       propyl                                                              2   0     3-(Pyridin-3-                                                                            3-Phenylpropyl                                                                          Phenyl                                                   yl)-propyl                                                          2   0     3-(Pyridin-2-                                                                            3-Phenylpropyl                                                                          Phenyl                                                   yl)-propyl                                                          2   0     3-(Pyridin-2-                                                                            3-Phenylpropyl                                                                          3,4,5-Trimethoxyphenyl                                   yl)-propyl                                                          2   0     3-(Pyridin-                                                                              3-Phenylpropyl                                                                          tert-Butyl                                               2yl)-propyl                                                         2   0     3-(Pyridin-3-                                                                            3-Phenylpropyl                                                                          3,4,5-Trimethoxyphenyl                                   yl)-propyl                                                                    N-oxide                                                             2   0     3-IN-(7-   3-Phenylpropyl                                                                          3,4,5-Trimethoxyphenyl                                   Azaindolyl)-                                                                  propyl                                                              2   0     3-(Pyridin-                                                                              3-(4-Methoxy-                                                                           3,4,5-Trimethoxyphenyl                                   3-yl)-propyl                                                                             phenyl)propyl                                            2   0     3-(N-Purinyl)                                                                            3-Phenylpropyl                                                                          3,4,5-Trimethoxyphenyl                                   propyl                                                              2   0     3-(4-Hydroxy-                                                                            3-Phenylpropyl                                                                          3,4,5-Trimethoxyphenyl                                   methyl-                                                                       phenyl)                                                                       propyl                                                              2   0     3-(Pyridin-3-                                                                            3-Phenylpropyl                                                                          3-Benzyloxyphenyl                                        yl)-propyl                                                          2   0     3-(Pyridin-3-                                                                            3-Phenylpropyl                                                                          3-Allyloxyphenyl                                         yl)-propyl                                                          2   0     3-(Pyridin-3-                                                                            3-Phenylpropyl                                                                          3-Isopropoxyphenyl                                       yl)-propyl                                                          2   0     3-(Thiophen-                                                                             3-Phenylpropyl                                                                          3,4,5-Trimethoxyphenyl                                   2-yl)-propyl                                                        2   0     3-(4-Carboxy-                                                                            3-Phenylpropyl                                                                          3,4,5-Trimethoxyphenyl                                   phenyl)                                                                       propyl                                                              2   0     3-Phenylbutyl                                                                            3-Phenylpropyl                                                                          3,4,5-Trimethoxyphenyl                         2   0     2-Hydroxy- 3-Phenylpropyl                                                                          3,4,6-Trimethoxyphenyl                                   methyl-                                                                       phenyl                                                              2   0     2-Allyloxy-                                                                              3-Phenylpropyl                                                                          3,4,5-Trimethoxyphenyl                                   phenyl                                                              2   0     3-(3-Hydroxy-                                                                            3-Phenylpropyl                                                                          3,4,5-Trimethoxyphenyl                                   methyl-                                                                       phenyl)                                                                       propyl                                                              2   0     3-(3-Carboxy-                                                                            3-Phenylpropyl                                                                          3,4,5-Trimethoxyphenyl                                   phenyl)                                                                       propyl                                                              2   0     3-Hydroxy- 3-Phenylpropyl                                                                          3,4,5-Trimethoxyphenyl                                   methyl-                                                                       phenyl                                                              2   0     2-Hydroxy- 3-Phenylpropyl                                                                          3,4,5-Trimethoxyphenyl                                   phenyl                                                              2   0     Pyridin-3-yl                                                                             3-Phenylpropyl                                                                          3,4,5-Trimethoxyphenyl                         2   0     3-(Thiophen-                                                                             4-Phenylbutyl                                                                           3,4,5-Trimethoxyphenyl                                   2-yl)-propyl                                                        2   0     5-Phenyl-  3-Phenylpropyl                                                                          3,4,5-Trimethoxyphenyl                                   pentyl                                                              ______________________________________                                    


7. A compound of formula (II): ##STR22## wherein n, m, B, D and U aredefined as follows:

    ______________________________________                                        n   m     B            D           U                                          ______________________________________                                        2   0     3-Allyloxypropyl                                                                           3-Phenylpropyl                                                                            3,4,5-Tri-                                                                    methoxyphenol                              2   0     3-[4-(N,N-Di 3-Phenylpropyl                                                                            3,4,5-Tri-                                           methylamine-             methoxyphenol                                        carbonyl)-phenyl]                                                             propyl                                                              2   0     3-14-(Morpholino-                                                                          3-Phenylpropyl                                                                            3,4,5-Tri-                                           4-carbonyl)              methoxyphenol                                        phenyl)-propyl                                                      2   0     4-Allyoxybutyl                                                                             3-Phenylpropyl                                                                            3,4,5-Tri-                                                                    methoxyphenol                              2   0     3-Allyloxy-  3-Phenylpropyl                                                                            3,4,5-Tri-                                           prop-1-ynyl              methoxyphenol                              2   0     3[4-(Piperi- 3-Phenylpropyl                                                                            3,4,5-Tri-                                           dine-1-carbonyl)         methoxyphenol                                        phenyl)-propyl                                                      2   0     5-Allyloxynonyl                                                                            3-Phenylpropyl                                                                            3,4,5-Tri-                                                                    methoxyphenol                              2   0     Methyl       3,5-Bis(benzyl-                                                                           3,4,5-Tri-                                                        oxy)phenyl  methoxyphenol                              2   0     2-Allyloxyethyl                                                                            3-Phenylpropyl                                                                            3,4,5-Tri-                                                                    methoxyphenol                              2   0     3-Allyloxy-(E)-                                                                            3-Phenylpropyl                                                                            3,4,5-Tri-                                           prop-l-onyl              methoxyphenol                              2   0     3-13-(Morpho-                                                                              3-Phenylpropyl                                                                            3,4,5-Tri-                                           lino-4-carbonyl)         methoxyphenol                                        phenyl]propyl                                                       2   0     Dec-9-enyl   3-Phenylpropyl                                                                            3,4,5-Tri-                                                                    methoxyphenol                              2   0     3-[4-(N-Benzyl                                                                             3-Phenylpropyl                                                                            3,4,5-Tri-                                           aminecarbonyl)-          methoxyphenol                                        phenyl]propyl                                                       2   0     3-[4-(Thiomorpho-                                                                          3-Phenylpropyl                                                                            3,4,5-Tri-                                           lino-4-carbonyl)-        methoxyphenol                                        phenyl]propyl                                                       2   0     3-(Morpholino-4-                                                                           3-Phenylpropyl                                                                            3,4,5-Tri-                                           carbonyl)phenyl-         methoxyphenol                              2   0     3-[4-(1-Methyl-                                                                            3-Phenylpropyl                                                                            3,4,5-Tri-                                           piperazine-4-            methoxyphenol                                        carbonyl)-phenyl]                                                             propyl                                                              2   0     3-[4-(1-Benzyl-                                                                            3-Phenylpropyl                                                                            3,4,5-Tri-                                           piperazine-4-            methoxyphenol                                        carbonyl)-phenyl]                                                             propyl                                                              2   0     3-[3-(N-Benzyl-                                                                            3-Phenylpropyl                                                                            3,4,5-Tri-                                           aminecarbonyl)-          methoxyphenol                                        phenylpropyl                                                        2   0     3-[4-(N-Pyridin-                                                                           3-Phenylpropyl                                                                            3,4,5-Tri-                                           2-ylaminecarbon-         methoxyphenol                                        yl)-phenyl]propyl                                                   2   0     Pryidin-3-yl 3-(Pyridin-3-yl)-                                                                         3,4,5-Tri-                                                        propyl      methoxyphenol                              2   0     Prop-2-enyl  3,4-Bis-(Pyridin-4-                                                                       3,4,5-Tri-                                                        ylmethoxy)phenyl                                                                          methoxyphenol                              2   0     Pyridin-3-yl 3-(Pyridin-4-yl-                                                                          3,4,5-Tri-                                                        methoxy)phenyl                                                                            methoxyphenol                              2   0     3-Phenylpropyl                                                                             3-(Pyridin-4-yl-                                                                          3,4,5-Tri-                                                        methoxy)phenyl                                                                            methoxyphenol                              2   0     3-Phenylpropyl                                                                             3,4-Bis-(Pyridin-4-                                                                       3,4,5-Tri-                                                        ylmethoxy)phenyl                                                                          methoxyphenol                              2   0     Methyl       3,4-Bis-(Pyridin-4-                                                                       3,4,5-Tri-                                                        ylmethoxy)phenyl                                                                          methoxyphenol                              2   0     3-Phenylpropyl                                                                             2,3,4-Tris-(Pyridin-                                                                      3,4,5-Tri-                                                        4-ylmethoxy)phenyl                                                                        methoxyphenol                              2   0     3-Phenylpropyl                                                                             3-(Morpholino-4-                                                                          3,4,5-Tri-                                                        carbonyl)-4-                                                                              methoxyphenol                                                     (Pyridin-4-yl-                                                                methoxy)phenyl                                         2   0     Methyl       3,4,5-Tris-(Pyridin-                                                                      3,4,5-Tri-                                                        4-ylmethoxy)phenyl                                                                        methoxyphenol                              2   0     3-Phenylpropyl                                                                             3,4,5-Tris-(Pyridin-                                                                      3,4,5-Tri-                                                        4-ylmethoxy)phenyl                                                                        methoxyphenol                              2   0     Methyl       3,5-Bis-(Pyridin-4-                                                                       3,4,5-Tri-                                                        ylmethoxy)phenyl                                                                          methoxyphenol                              2   0     3,5-Bis-(Pyridin-                                                                          Methyl      3,4,5-Tri-                                           4-ylmethoxy)             methoxyphenol                                        phenyl                                                              2   0     Methyl       3,5-Bis-(Pyridin-4-                                                                       3,4,5-Tri-                                                        y[methoxy)-4-                                                                             methoxyphenol                                                     Methyl-phenyl                                          2   0     Ethyl        3,4,5-Tris-(Pyridin-                                                                      3,4,5-Tri-                                                        4-ylmethoxy)phenyl                                                                        methoxyphenol                              2   0     3,4,5-Tris-  Ethyl       3,4,5-Tri-                                           (Pyridin-4-yl-           methoxyphenol                                        methoxy)phenyl                                                      2   0     Prop-2-enyl  3,4,5-Tris-(Pyridin-                                                                      3,4,5-Tri-                                                        4-ylmethoxy)phenyl                                                                        methoxyphenol                              2   0     Methyl       3,4,6-Tris-(Pyridin-                                                                      3,4-Di-                                                           4-ylmethoxy)phenyl                                                                        methoxyphenyl                              2   0     Ethenyl      3,4,5-Tris-(Pyridin-                                                                      3,4,5-Tri-                                                        4-ylmethoxy)phenyl                                                                        methoxyphenol                              2   0     3,4,5-Tris-  Ethenyl     3,4,5-Tri-                                           (Pyridin-4-              methoxyphenol                                        ylmethoxy)phenyl                                                    2   0     Propyl       3,4,5-Tris-(Pyridin-                                                                      3,4,5-Tri-                                                        4-ylmethoxy)phenyl                                                                        methoxyphenol                              2   0     3,4,5-Tris-  Propyl      3,4,5-Tri-                                           (Pyridin-4-              methoxyphenol                                        ylmethoxy)phenyl                                                    2   0     Methyl       3,4,5-Tris- 3,4,5-Tri-                                                        (Thiophen-3-yl-                                                                           methoxyphenol                                                     methoxy)phenyl                                         2   0     3,4,5-Tris-  Methyl      3,4,5-Tri-                                           (Thio-phen-3-            methoxyphenol                                        ylmethoxy)-                                                                   phenyl                                                              2   0     Methyl       2-isopropoxy-3,4-                                                                         3,4,5-Tri-                                                        Bis-(Pyridin-4-                                                                           methoxyphenol                                                     ylmethoxy)-phenyl                                      2   0     2-Isopropoxy-                                                                              Methyl      3,4,5-Tri-                                           3,4-Bis-(Pyridin-        methoxyphenol                                        4-yl-methoxy)                                                                 phenyl                                                              1   0     Methyl       3,4,5-Tris-(Pyridin-                                                                      3,4,5-Tri-                                                        4-ylmethoxy)phenyl                                                                        methoxyphenol                              1   0     3,4,5-Tris-  Methyl      3,4,5-Tri-                                           (Pyridin-4-              methoxyphenol                                        ylmethoxy)phenyl                                                    2   0     Methyl       3,4,5-Tris- 3,4,5-Tri-                                                        (Pyrimidin-4-                                                                             methoxyphenol                                                     ylmethoxy)phenyl                                       2   0     Benzyloxymethyl                                                                            Benzyloxyphenyl                                                                           3,4,5-Tri-                                                                    methoxyphenol                              2   0     Methyl       3,4,5-Tris-(Benzyl-                                                                       3,4,5-Tri-                                                        oxy)phenyl  methoxyphenol                              2   0     3-Phenylpropyl                                                                             3-(Pyridin-3-yl-                                                                          3,4,5-Tri-                                                        carbonyl)phenyl                                                                           methoxyphenol                              2   0     3-(Pyridin-3-yl-                                                                           3-Phenylpropyl                                                                            3,4,5-Tri-                                           carbonyl)phenyl          methoxyphenol                              2   0     3-Phenylpropyl                                                                             3-(Pyridin-4-yl-                                                                          3,4-Di-                                                           methoxy)phenyl                                                                            methoxyphenol                              2   0     3-Phenylpropyl                                                                             3-(Pyridin-4-yl-                                                                          4-Benzyloxy-                                                      carbonyl)phenyl                                                                           3,5-Dimethoxy-                                                                phenyl                                     2   0     3-Phenylpropyl                                                                             3-(Pyridin-4-yl-                                                                          4-Allylyoxy-3,5-                                                  carbonyl)phenyl                                                                           Dimethoxy-                                                                    phenyl                                     2   0     3-Phenylpropyl                                                                             3-(Pyridin-4-yl-                                                                          3-Benzyloxy-4-                                                    carbonyl)phenyl                                                                           methoxyphenyl                              2   0     3-Phenylpropyl                                                                             3-(Pyridin-4-yl-                                                                          3-Allyloxy-4-                                                     carbonyl)phenyl                                                                           methoxyphenyl                              2   0     3-Phenylpropyl                                                                             3-(Pyridin-4-yl-                                                                          3-[3-Phenyl-(E)-                                                  carbonyl)phenyl                                                                           prop-2-enyl]-4-                                                               methoxyphenyl                              2   0     3-Phenylpropyl                                                                             4-(Pyridin-4-yl-                                                                          4-Benzyloxy-                                                      carbonyl)phenyl                                                                           3,5-Dimethoxy-                                                                phenyl                                     2   0     3-Phenylpropyl                                                                             4-(Pyridin-4-yl-                                                                          3-Benzyloxy-4-                                                    carbonyl)phenyl                                                                           methoxyphenyl                              2   0     3-Phenylpropyl                                                                             3-(Pyridin-4-yl-                                                                          3,4,5-Tri-                                                        carbonyl)phenyl                                                                           methoxyphenol                              2   0     3-Phenylpropyl                                                                             3-(Pyridin-4-yl-                                                                          3,4-Di-                                                           carbonyl)phenyl                                                                           methoxyphenyl                              2   0     3-Phenylpropyl                                                                             Phenyl      3-Benzyloxy-4-                                                                methoxyphenyl                              2   0     3-Phenylpropyl                                                                             Phenyl      4-Benzyloxy-                                                                  3,5-Dimethoxy-                                                                phenyl                                     1   0     3-(Pyridin-3-                                                                              3-Phenylpropyl                                                                            tert-Butyl                                           yl)-propyl                                                          2   0     3-(Pyridin-3-                                                                              3-(Pyridin-3-yl)-                                                                         3,4,5-Tri-                                           yl)-propyl   propyl      methoxyphenol                              1   0     Benzyloxymethyl                                                                            Benzyloxyphenyl                                                                           3,4,5-Tri-                                                                    methoxyphenol                              1   0     3-(Pyridin-3-                                                                              3-(Pyridin-3-yl)-                                                                         3,4,5-Tri-                                           yl-propyl    propyl      methoxyphenol                              2   0     3-(Pyridin-3-                                                                              3-(Pyridin-3-yl)-                                                                         Isopropyl                                            yl)-propyl   propyl                                                 2   0     3-(Pyridin-3-                                                                              3-(Pyridin-3-yl)-                                                                         Thiophen-2-yl                                        yl)-                                                                2   0     3-(Pyridin-3-                                                                              3-(Pyridin-3-yl)-                                                                         3,4-Methylene-                                       yl)-propyl   propyl      dioxyphenyl                                2   0     3-(Pyridin-3-                                                                              3-(Pyridin-3-yl)-                                                                         3,4-Methylene-                                       yl)-prop-2-ynyl                                                                            prop-2-ynyl dioxyphenyl                                2   0     3-(Pyridin-3-                                                                              3-(Pyridin-3-yl)-                                                                         3,4,5-Tri-                                           yl)-prop-2-ynyl                                                                            prop-2-ynyl methoxyphenol                              2   0     3-(Pyridin-2-                                                                              3-(Pyridin-2-yl)-                                                                         3,4,5-Tri-                                           yl-propyl    propyl      methoxyphenol                              2   0     Isopropyl    3,4,5-Tris-(Pyridin-                                                                      3,4,5-Tri-                                                        4-ylmethoxy)phenyl                                                                        methoxyphenol                              2   0     3,4,5-Tris-  Isopropyl   3,4,5-Tri-                                           (Pyridin-4-              methoxyphenol                                        ylmethoxy)phenyl                                                    2   0     Prop-2-enyl  3,4,5-Tris-(Pyridin-                                                                      3,4,5-Tri-                                                        4-ylmethoxy)phenyl                                                                        methoxyphenol                              2   0     3,4,5-Tris-  Prop-2-enyl 3,4,5-Tri-                                           (Pyridin-4-              methoxyphenol                                        ylmethoxy)phenyl                                                    ______________________________________                                    


8. The compound according to claim 1, wherein, in formula (I), at leastone of B or D is independently represented by the formula --(CH₂)_(r)--(X)--(CH₂)_(s) --Ar₂, wherein:r is 0-4; s is 0-1; and each X isindependently selected from the group consisting of CH₂, O, S, SO, andSO₂.
 9. A compound selected from the group consistingof:(S)-1-(2-oxo-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxylicacid-4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)butyl ester;(R)-1-(2-oxo-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxylicacid-4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)butyl ester;pharmaceutically acceptable derivatives thereof, and mixtures thereof.10. A pharmaceutical composition comprising: a compound selectedfrom:(S)-1-(2-oxo-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxylicacid-4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)butyl ester;(R)-1-(2-oxo-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxylicacid-4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)butyl ester;pharmaceutically acceptable derivatives thereof, mixtures thereof, othercompounds of formula (II) and other compounds of formula (I), saidcompound being present in an amount effective to treat or preventmulti-drug resistance; and a pharmaceutically acceptable carrier,adjuvant or vehicle.
 11. The pharmaceutical composition according toclaim 10, further comprising a chemotherapeutic agent.
 12. Thepharmaceutical composition according to claim 10 or 11, furthercomprising a chemosensitizer other than a compound according to formula(I).
 13. A pharmaceutical composition comprising: a compound selectedfrom:(S)-1-(2-oxo-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxylicacid-4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)butyl ester;(R)-1-(2-oxo-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxylicacid-4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)butyl ester;pharmaceutically acceptable derivatives thereof, mixtures thereof, othercompounds of formula (II) and other compounds of formula (I), saidcompound being present in an amount effective to reduce, suppress orprevent an immune response; and a pharmaceutically acceptable carrier,adjuvant or vehicle.
 14. The pharmaceutical composition according toclaim 13, further comprising an immunosuppressant selected from thegroup consisting of cyclosporin A, rapamycin, FK-506,15-deoxyspergualin, OKT3 and azathioprine.
 15. The pharmaceuticalcomposition according to claim 13 or 14, further comprising animmunosuppressant selected from the group consisting of micophenolicacid and brequinar.
 16. The pharmaceutical composition according toclaim 13 or 14, further comprising a steroid.
 17. A method for treatingor preventing multi-drug resistance in a patient comprising the step ofadministering to said patient a pharmaceutical composition comprising:acompound in an amount effective to treat or prevent said multi-drugresistance; and a pharmaceutically acceptable carrier, adjuvant orvehicle;said compound being a compound of formula (I): ##STR23##wherein: A is CH₂, oxygen, NH or N--(C1-C4 alkyl); B and D areindependently:(i) hydrogen, Ar₁, (C1-C10)-straight or branched alkyl,(C2-C10)-straight or branched alkenyl or alkynyl, (C5-C7)-cycloalkylsubstituted (C1-C6)-straight or branched alkyl, (C2-C6)-straight orbranched alkenyl or alkynyl, (C5-C7)-cycloalkenyl substituted(C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenylor alkynyl, or Ar₁ substituted (C1-C6)-straight or branched alkyl,(C2-C6)-straight or branched alkenyl or alkynyl wherein, in each case,any one of the CH₂ groups of said alkyl, alkenyl or alkynyl chains maybe optionally replaced by a heteroatom selected from the groupconsisting of O, S, SO, SO₂, N, and NR, wherein R is selected from thegroup consisting of hydrogen, (C1-C4)-straight or branched alkyl,(C2-C4)-straight or branched alkenyl or alkynyl, and (C1-C4) bridgingalkyl wherein a bridge is formed between the nitrogen and a carbon atomof said heteroatom-containing chain to form a ring, and wherein saidring is optionally fused to an Ar₁ group; or ##STR24## (ii) wherein Q ishydrogen, (C1-C6)-straight or branched alkyl or (C2-C6)-straight orbranched alkenyl or alkynyl; wherein T is Ar₁ or substituted 5-7membered cycloalkyl with substituents at positions 3 and 4 which areindependently selected from the group consisting of oxo, hydrogen,hydroxyl, O--(C1-C4)-alkyl, and O--(C2-C4)-alkenyl;wherein Ar₁ is acarboxylic aromatic group selected from the group consisting of phenyl,1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, and anthracenyl;or a heterocyclic aromatic group selected from the group consisting of2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl,pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl,indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl,benzo[b]furanyl, benzo[b]thiophenyl, 1H-indazolyl, benzimidazolyl,benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl,cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl,phenothiazinyl, and phenoxazinyl; wherein any occurrence of Ar₁ maycontain one to three substituents which are independently selected fromthe group consisting of hydrogen, halogen, hydroxyl, hydroxymethyl,nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)-straight or branchedalkyl, (C2-C6)-straight or branched alkenyl, O--[(C1-C4)-straight orbranched alkyl], O--[(C2-C4)-straight or branched alkenyl], O-benzyl,O-phenyl, 1,2-methylenedioxy, amino, carboxyl, N-[(C1-C5)-straight orbranched alkyl or (C2-C5)-straight or branched alkenyl)carboxamides,N,N-di-[(C1-C5)-straight or branched alkyl or (C2-C5)-straight orbranched alkenyl)]carboxamides, N-morpholinocarboxamide,N-benzylcarboxamide, N-thiomorpholinocarboxamide,N-picolinoylcarboxamide, O--X, CH₂ --(CH₂)_(q) --X, O--(CH₂)_(q) --X,(CH₂)_(q) --O--X, and CH═CH--X;wherein X is 4-methoxyphenyl, 2-pyridyl,3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazoyl,isoxazoyl, 2-methylthiazoyl, thiazoyl, 2-thienyl, 3-thienyl, orpyrimidyl; and q is 0-2; L is U; M is either oxygen or CH--U; providedthat if L is hydrogen, then M is CH--U or if M is oxygen, then L is nothydrogen;wherein U is hydrogen, O--[(C1-C4)-straight or branched alkyl]or O--[(C2-C4)straight or branched alkenyl], (C1-C6)-straight orbranched alkyl or (C2-C6)-straight or branched alkenyl,(C5-C7)-cycloalkyl or (C5-C7)-cycloalkenyl substituted with(C1-C4)-straight or branched alkyl or (C2-C4)-straight or branchedalkenyl, [(C1-C4)-alkyl or (C2-C4)-alkenyl]-Y or Y;wherein Y is selectedfrom the group consisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl,azulenyl, fluorenyl, anthracenyl, 2-pyrrolinyl, 3-pyrrolinyl,pyrolidinyl, 1,3-dioxolyl, 2-imidazolinyl, imidazolidinyl, 2H-pyranyl,4H-pyranyl, piperidyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl,thiomorpholinyl, piperazinyl, quinuclidinyl, and heterocyclic aromaticgroups as defined above; wherein Y may contain one to three substituentswhich are independently selected from the group consisting of hydrogen,halogen, hydroxyl, hydroxymethyl, nitro, trifluoromethyl,trifluoromethoxy, (C1-C6)-straight or branched alkyl, (C2-C6)-straightor branched alkenyl, O--[(C1-C4)-straight or branched alkyl],O--[(C2-C4)-straight or branched alkenyl], O-benzyl, O-phenyl,1,2-methylenedioxy, amino, and carboxyl; J and K are taken together withthe N and C atoms to which they are respectively attached to form a 5-7membered heterocyclic ring containing only one N atom; and m is 0-3. 18.A method for treating or preventing multi-drug resistance in a patientcomprising the step of administering to said patient a pharmaceuticalcomposition comprising:a compound in an amount effective to treat orprevent said multi-drug resistance; and a pharmaceutically acceptablecarrier, adjuvant or vehicle;said compound being a compound of formula(I): ##STR25## wherein: A is CH₂, oxygen, NH or N--(C1-C4 alkyl); B andD are independently(i) Ar₁, (C1-C10)-straight or branched alkyl,(C2-C10)-straight or branched alkenyl or alkynyl,(C5-C7)-cycloalkyl-substituted (C1-C6)-straight or branched alkyl or(C2-C6)-straight or branched alkenyl or alkynyl,(C5-C7)-cycloalkenyl-substituted (C1-C6)-straight or branched alkyl or(C2-C6)-straight or branched alkenyl or alkynyl, or Ar₁ -substituted(C1-C6)-straight or branched alkyl or (C2-C6)-straight or branchedalkenyl or alkynyl wherein, in each case, any one of the CH₂ groups ofsaid alkyl, alkenyl or alkynyl chains may be optionally replaced by aheteroatom selected from the group consisting of O, S, SO, SO₂ ; or##STR26## (ii) wherein Q is hydrogen, (C1-C6)-straight or branched alkylor (C2-C6)-straight or branched alkenyl or alkynyl; wherein T is Ar₁ orsubstituted 5-7 membered cycloalkyl with substitutents at positions 3and 4 which are independently selected from the group consisting of oxo,hydrogen, hydroxyl, O--(C1-C4)-alkyl or O--(C2-C4)-alkenyl;wherein Ar₁is a carboxylic aromatic group selected from the group consisting ofphenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, andanthracenyl; or a heterocyclic aromatic group selected from the groupconsisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl,1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl,pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl,indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl,benzo[b]thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl,purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl,pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, andphenoxazinyl; wherein any occurrence of Ar₁ may contain one to threesubstituents which are independently selected from the group consistingof hydrogen, halogen, hydroxyl, nitro, trifluoromethyl,trifluoromethoxy, (C1-C6)-straight or branched alkyl, (C2-C6)-straightor branched alkenyl, O--((C1-C4)-straight or branched alkyl),O--((C2-C4)-straight or branched alkenyl), O-benzyl, O-phenyl,1,2-methylenedioxy, amino, carboxyl, N-((C1-C5)-straight or branchedalkyl or (C2-C5)-straight or branched alkenyl)carboxamides,N,N-di-((C1-C5)-straight or branched alkyl or (C2-C5)-straight orbranched alkenyl)carboxamides, N-morpholinocarboxamide,N-benzylcarboxamide, N-thiomorpholinocarboxamide,N-picolinoylcarboxamide, O--X, CH₂ --(CH₂)_(q) --X, O--(CH₂)_(q) --X,(CH₂)_(q) --O--X, and CH═CH--X;wherein X is 4-methoxyphenyl, 2-pyridyl,3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazoyl,isoxazoyl, 2-methylthiazoyl, thiazoyl, 2-thienyl, 3-thienyl, orpyrimidyl; and q is 0-2; L is U; M is either oxygen or CH--U; providedthat if L is hydrogen, then M is CH--U or if M is oxygen, then L is nothydrogen;wherein U is hydrogen, O--((C1-C4)-straight or branched alkyl)or O--((C2-C4)straight or branched alkenyl), (C1-C6)-straight orbranched alkyl or (C2-C6)-straight or branched alkenyl,(C5-C7)-cycloalkyl or (C5-C7)-cycloalkenyl substituted with(C1-C4)-straight or branched alkyl or (C2-C4)-straight or branchedalkenyl, [(C1-C4)-alkyl or (C2-C4)-alkenyl]-Y or Y;wherein Y is acarboxylic aromatic group selected from the group consisting of phenyl,1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl; or aheterocyclic aromatic group as defined above; wherein Y may contain oneto three substituents which are independently selected from the groupconsisting of hydrogen, halogen, hydroxyl, nitro, trifluoromethyl,trifluoromethoxy, (C1-C6)-straight or branched alkyl, (C2-C6)-straightor branched alkenyl, O--((C1-C4)-straight or branched alkyl),O--((C2-C4)-straight or branched alkenyl), O-benzyl, O-phenyl,1,2-methylenedioxy, amino, and carboxyl; J and K are taken together withthe N and C atoms to which they are respectively attached to form a 5-7membered heterocyclic ring containing only one N atom; and m is 0-3. 19.The method according to claim 17 or 18, wherein at least one of B or Dis independently selected from the group consisting of (C2-C10)-straightor branched alkynyl; (C5-C7)-cycloalkyl substituted (C2-C6)-straight orbranched alkynyl; (C5-C7)-cycloalkenyl substituted (C2-C6)-straight orbranched alkynyl; and Ar₁ -substituted (C2-C6)-straight or branchedalkynyl.
 20. The method according to claim 17 or 18, wherein, at leastone of B or D is independently selected from the group consisting ofAr', Ar'-substituted (C1-C6)-straight or branched alkyl, andAr'-substituted (C2-C6)-straight or branched alkenyl or alkynyl;whereinAr' is an Ar group substituted with one to three substituents which areindependently selected from the group consisting of N-(straight orbranched (C1-C5)-alkyl or (C2-C5)-alkenyl) carboxamides,N,N-di-(straight or branched (C1-C5)-alkyl or(C2-C5)-alkenyl)carboxamides, N-morpholinocarboxamide,N-benzylcarboxamide, N-thiomorpholinocarboxamide,N-picolinoylcarboxamide, O--X, CH₂ --(CH₂)_(q) --X, O--(CH₂)_(q) --X,(CH₂)_(q) --O--X, and CH═CH--X;wherein X is 4-methoxyphenyl, 2-pyridyl,3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazoyl,isoxazoyl, 2-methylthiazoyl, thiazoyl, 2-thienyl, 3-thienyl, orpyrimidyl; and q is 0-2.
 21. The method according to claim 17, whereinat least one of B or D is independently represented by the formula--(CH₂)_(r) --(X)--(CH₂)_(s) --Ar₁, wherein:r is 0-4; s is 0-1; and eachX is independently selected from the group consisting of CH₂, O, S, SO,SO₂, N, and NR,wherein R is selected from the group consisting ofhydrogen, (C1-C4)-straight or branched alkyl, (C2-C4)-straight orbranched alkenyl or alkynyl, and (C1-C4) bridging alkyl, wherein abridge is formed between the nitrogen atom and the Ar₁ group.
 22. Themethod according to claim 17 or 18, wherein said compound of formula (I)is selected from the group consistingof:(S)-1-(2-oxo-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxylicacid-4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)butyl ester;(R)-1-(2-oxo-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxylicacid-4-pyridin-3-yl-1-(3-pyridin-3-yl-propyl)butyl ester;pharmaceutically acceptable derivatives thereof, and mixtures thereof.23. A method for reducing, suppressing or preventing an immune responsein a mammal comprising the step of administering to said mammal apharmaceutical composition comprising;a compound in an amount effectiveto reduce, suppress or prevent said immune response; and apharmaceutically acceptable carrier, adjuvant or vehicle;said compoundbeing a compound of formula (I) as defined in claim
 1. 24. The methodaccording to claim 23, further comprising the step of administering tosaid mammal an immunosuppressant selected from the group consisting ofcyclosporin A, rapamycin, FK-506, 15-deoxyspergualin, OKT3 andazathioprine.
 25. The method according to claim 23, further comprisingthe step of administering a steroid to said mammal.
 26. The methodaccording to any one of claims 19, 18 or 23, wherein the compound isadministered orally.
 27. The method according to claim 17 or 18, whereinthe compound is not substantially immunosuppressive at the dosage levelrequired to cause chemosensitization.